Cell proliferation inhibitors

ABSTRACT

Compounds having formula (I)  
                 
inhibit cellular proliferation. Processes for the preparation of the compounds, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.10/301,427, filed Nov. 21, 2002, which is a divisional of Ser. No.09/579,705, filed May 26, 2000, which is a continuation-in-part ofprovisional U.S. Patent Application Ser. No. 60/136,542, filed May 28,1999.

TECHNICAL FIELD

The present invention relates to compounds useful for treatingpathological states, which arise from or are exacerbated by cellproliferation, to pharmaceutical compositions comprising thesecompounds, and to methods of inhibiting cell proliferation in a mammal.

BACKGROUND OF THE INVENTION

Neoplastic diseases, characterized by the proliferation of cells whichare not subject to normal cell proliferating controls, are a major causeof death in humans and other mammals. Cancer chemotherapy has providednew and more effective drugs to treat these diseases and has alsodemonstrated that drugs which disrupt microtubule synthesis areeffective in inhibiting the proliferation of neoplastic cells.

Microtubules play a key role in the regulation of cell architecture,metabolism, and division. The microtubule system of eucaryotic cellscomprises a dynamic assembly and disassembly matrix in whichheterodimers of tubulin polymerize to form microtubules in both normaland neoplastic cells. Within noeplastic cells, tubulin is polymerizedinto microtubules which form the mitotic spindle. The microtubules arethen depolymerized when the mitotic spindle's use has been fulfilled.Agents which disrupt the polymerization or depolymerization ofmicrotubules in neoplastic cells, thereby inhibiting the proliferationof these cells, comprise some of the most effective cancerchemotherapeutic agents in use.

Because of the pivotal role played by cell proliferation, agents whichinhibit microtubule polymerization have been the subject of activecurrent research for their clinical potential. See, for example, U.S.Pat. Nos. 5,767,283, 5,721,246, 5,610,320, FR 2,729,421-A1, andWO96/27295. But there is still a need for tubulinpolymerization-inhibiting compounds with modified or improved profilesof activity.

SUMMARY OF THE INVENTION

In one embodiment of the present invention are disclosed microtubulepolymerization-inhibiting compounds represented by formula (I)

or pharmaceutically acceptable salts or prodrugs thereof, wherein

-   L¹ is selected from the group consisting of    -   (1) —S(O)₂O—,    -   (2) —OS(O)₂—,    -   (3) —NR⁷SO₂—, wherein R⁷ is selected from the group consisting        of        -   (a) hydrogen,        -   (b) hydroxy,        -   (c) amidinyl,        -   (d) a nitrogen-protecting group,        -   (e) alkanoyl,        -   (f) alkyl,        -   (g) alkenyl,        -   (h) alkynyl,        -   (i) cycloalkyl,        -   (j) cycloalkylalkyl,        -   (k) cycloalkenyl,        -   (l) cycloalkenylalkyl,        -   (m) aryloyl,        -   (n) alkoxy,        -   wherein (e)-(n) can be optionally substituted with one, two,            or three substituents independently selected from the group            consisting of            -   (i) hydroxyl,            -   (ii) halo,            -   (iii) cyano,            -   (iv) azido,            -   (v) carboxy,            -   (vi) amidinyl,            -   (vii) alkyl,            -   (viii) aryl,            -   (ix) oxo,            -   (x) heteroaryl,            -   (xi) heterocycloalkyl,            -   (xii) —NR^(c)R^(d), wherein R^(c) and R^(d) are                independently selected from the group consisting of                -   (1′) hydrogen,                -   (2′) alkyl,                -   (3′) aryl,                -   and                -   (4′) alkoxyalkyl,            -   and            -   (xiii) -(alkylene)-NR^(c)R^(d),            -   wherein for (x) and (xi), the heteroaryl and the                heterocycloalkyl can be optionally substituted with 1,                2, or 3 substituents independently selected from the                group consisting of                -   (1′) alkyl,                -   and                -   (2′) a nitrogen protecting group,        -   (o) heterocycloalkyloyl, wherein the heterocycloalkyloyl can            be optionally substituted with 1, 2, or 3 substituents            independently selected from the group consisting of            -   (i) alkyl,            -   and            -   (ii) a nitrogen protecting group,        -   and        -   (p) —(CH₂)_(x)NR^(A)R^(B), wherein x is 0-6, and R^(A) and            R^(B) are independently selected from the group consisting            of            -   (i) hydrogen,            -   (ii) alkyl,            -   (iii) alkenyl,            -   (iv) alkynyl,            -   (v) cycloalkyl,            -   (vi) cycloalkylalkyl,            -   (vii) cycloalkenyl,            -   and            -   (viii) cycloalkenylalkyl,    -   (4) —SO₂NR⁷—, wherein R⁷ is defined above,    -   (5) —S(O)CR¹²R¹³—, wherein R¹² and R¹³ are independently        selected from the group consisting of        -   (a) hydrogen,        -   (b) alkyl,        -   (c) alkenyl,        -   and        -   (d) alkynyl,    -   (6) —SO₂CR¹²R¹³—,    -   (7) —SCR¹²R¹³—,    -   (8) —CR¹²R¹³S(O)—,    -   (9) —CR¹²R¹³SO₂—,    -   and    -   (10) —CR¹²R¹³S—,    -   wherein (1)-(10) are shown with their left ends attached to R¹        and their right ends attached to the phenyl ring;-   R¹ is aryl or heteroaryl, wherein the aryl or the heteroaryl can be    optionally substituted with 1, 2, 3, 4,or 5 substituents    independently selected from the group consisting of    -   (a) oxo,    -   (b) azido,    -   (c) carboxy,    -   (d) carboxaldehyde,    -   (e) cyano,    -   (f) halo,    -   (g) hydroxy,    -   (h) nitro,    -   (i) perfluoroalkyl,    -   (j) perfluoroalkoxy,    -   (k) alkyl,    -   (l) alkenyl,    -   (m) alkynyl,    -   (n) alkanoyloxy,    -   (o) alkoxycarbonyl,    -   (p) cycloalkyl,    -   (q) cycloalkylalkyl,    -   (r) cycloalkenyl,    -   (s) cycloalkenylalkyl,    -   (t) alkanoyl,    -   (u) alkoxy,    -   (v) cycloalkoxy,    -   (w) aryloxy,    -   (x) heteroaryloxy,    -   (y) thioalkoxy    -   (z) alkylsulfinyl,    -   (aa) alkylsulfonyl,    -   (bb) —NR⁸R⁹, wherein R⁸ and R⁹ are independently selected from        the group consisting of        -   (i) hydrogen        -   (ii) alkyl,        -   (iii) arylalkyl,        -   and        -   (iv) alkanoyl, wherein the alkanoyl can be optionally            substituted with 1 or 2 substituents independently selected            from the group consisting of            -   (1′) halo            -   (2′) hydroxy,            -   and            -   (3′) —NR¹⁰R¹¹ wherein R¹⁰ and R¹¹ are independently                hydrogen or alkyl,    -   and    -   (cc) —SO₂NR⁸R⁹, wherein R⁸ and R⁹ are defined above;-   R² and R⁶ are independently selected from the group consisting of    -   (1) hydrogen,    -   (2) alkyl,    -   (3) alkoxy,    -   (4) thioalkoxy;    -   and    -   (5) hydroxy,-   and-   R³, R⁴, and R⁵ are independently selected from the group consisting    of    -   (1) alkyl,    -   (2) alkoxy,    -   (3) thioalkoxy,    -   and    -   (4) hydroxy;-   all of the foregoing with the proviso that combinations wherein L¹    is —NR⁷SO₂— and R¹ is    -   (1) unsubstituted or substituted 1H-indoly-7-yl,    -   (2) phenyl which is 2-monosubstituted with —NR⁸R⁹,    -   (3) pyrid-3-yl which is 2-monosubstituted with —NR⁸R⁹,    -   or    -   (4) pyrimidin-5-yl which is 4-monosubstituted with —NR⁸R⁹,        are excluded therefrom.

In a preferred embodiment of the invention are compounds wherein L¹ is—SO₂NR⁷—, and R⁷ is defined above.

In another preferred embodiment of the invention are compounds whereinR¹ is aryl.

In another preferred embodiment of the invention are compounds whereinR¹ optionally substituted heteroaryl, particularly N-methyl substituted1H-indolyl.

In another preferred embodiment of the invention are compounds whereinR⁷ is substituted alkanoyl, substituted aryloyl, or optionallysubstituted heterocycloalkyloyl.

In another preferred embodiment of the invention are compounds whereinL¹ is —NR⁷SO₂—, and R⁷ is defined above.

In another preferred embodiment of the invention are compounds whereinL¹ is —SO₂CR¹²R¹³—.

In another preferred embodiment of the invention are compounds whereinL¹ is —SCR¹²R¹³—.

In another preferred embodiment of the invention are compounds whereinL¹ is —CR¹²R¹³S(O)—.

In another preferred embodiment of the invention are compounds whereinL¹ is —CR¹²R¹³SO₂—.

In another preferred embodiment of the invention are compounds whereinL¹ is —CR¹²R¹³S—.

In yet another preferred embodiment of the invention are compoundswherein L¹ is —OSO₂—.

In still yet another preferred embodiment of the invention are compoundswherein L¹ is —SO₂O—.

In another embodiment of the invention are disclosed methods ofinhibiting polymerization of tubulin in a mammal in recognized need ofsuch treatment comprising administering an effective amount of acompound having formula (I).

In yet another embodiment of the invention are disclosed methods oftreating cancer in a mammal in recognized need of such treatmentcomprising administering an effective amount of a compound havingformula (I).

In still yet another embodiment of the invention are disclosedpharmaceutical compositions containing compounds having formula (I).

DETAILED DESCRIPTION OF THE INVENTION

Definition of Terms

The term “alkanoyl,” as used herein, refers to an alkyl group attachedto the parent molecular group through a carbonyl group. The alkanoylgroups of this invention can be optionally substituted.

The term “alkanoyloxy,” as used herein, refers to an alkanoyl groupattached to the parent molecular group through an oxygen atom.

The term “alkenyl,” as used herein, refers to a monovalent straight orbranched chain group of two to six carbon atoms containing at least onecarbon-carbon double bond. The alkenyl groups of this invention can beoptionally substituted.

The term “alkoxy,” as used herein, refers to an alkyl group attached tothe parent molecular group through an oxygen atom. The alkoxy groups ofthis invention can be optionally substituted.

The term “alkoxyalkyl,” as used herein, refers to an alkoxy groupattached to the parent molecular moiety through an alkyl group.

The term “alkoxycarbonyl,” as used herein, refers to an alkoxy groupattached to the parent molecular group through a carbonyl group.

The term “alkyl,” as used herein, refers to a monovalent group of one tosix carbon atoms derived from a straight or branched chain saturatedhydrocarbon. The alkyl groups of this invention can be optionallysubstituted.

The term “alkylating agent,” as used herein, represents a reagentcapable of donating an alkyl group during the course of a reaction.Examples of alkylating agents include methyl triflate, dimethyl sulfate,iodomethane, bromobutane, bromopropane, and the like.

The term “alkylene,” as used herein, refers to a saturated divalenthydrocarbon group derived from a straight or branched chain saturatedhydrocarbon by the removal of two hydrogen atoms.

The term “alkylsulfinyl,” as used herein, refers to an alkyl groupattached to the parent molecular group through an —S(O)— group.

The term “alkylsulfonyl,” as used herein, refers to an alkyl groupattached to the parent molecular group through an —SO₂— group.

The term “alkynyl,” as used herein, refers to a monovalent straight orbranched chain group of two to six carbon atoms containing at least onecarbon-carbon triple bond. The alkynyl groups of this invention can beoptionally substituted.

The term “amidinyl,” as used herein, refers to an —NR¹⁰R¹¹ group,wherein R¹⁰ and R¹¹ are defined above, connected to the parent moleculargroup through an imine.

The term “aryl,” as used herein, refers to a mono- orbicyclic-carbocyclic ring system having at least one aromatic ring. Arylgroups are exemplified by those derived from phenyl, naphthyl,1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl,indenyl, azulenyl, and troponyl. Bicyclic aryl groups of this inventioncan be attached to the parent molecular group through either a saturatedor unsaturated part of the group. The aryl groups of this invention canbe optionally substituted.

The term “arylalkyl,” as used herein, refers to an alkyl group to whichis attached at least one aryl group.

The term “aryloxy,” as used herein, refers to an aryl group attached tothe parent molecular group through an oxygen atom.

The term “aryloyl,” as used herein, refers to an aryl group attached tothe parent molecular moiety through a carbonyl group. The aryloyl groupsof this invention can be optionally substituted.

The term “azido,” as used herein, refers to —N₃.

The term “base,” as used herein, represents a reagent capable ofaccepting protons during the course of a reaction. Examples of basesinclude carbonates such as potassium carbonate, potassium bicarbonatesodium carbonate, sodium bicarbonate, and cesium carbonate; halides suchas cesium fluoride; phosphates such as potassium phosphate, potassiumdihydrogen phosphate, and potassium hydrogen phosphate; hydroxides suchas lithium hydroxide, sodium hydroxide, and potassium hydroxide;disilylamides such as lithium hexamethyldisilazide, potassiumhexamethyldisilazide, and sodium hexamethyldisilazide; trialkylaminessuch as triethylamine and diisopropylamine; heterocyclic amines such asimidazole, pyridine, pyridazine, pyrimidine, and pyrazine; bicyclicamines such as DBN and DBU; and hydrides such as lithium hydride, sodiumhydride, and potassium hydride. The base chosen for a particularconversion depends on the nature of the starting materials, the solventor solvents in which the reaction is conducted, and the temperature atwhich the reaction is conducted.

The term “carboxaldehyde,” as used herein, refers to —CHO.

The term “carbonyl,” as used herein, refers to —C(O)—.

The term “carboxy,” as used herein, refers to —CO₂H.

The term “cyano,” as used herein, refers to —CN.

The term “cycloalkenyl,” as used herein, refers to a monovalent cyclicor bicyclic hydrocarbon of four to twelve carbon atoms having at leastone carbon-carbon double bond.

The term “cycloalkenylalkyl,” as used herein, refers to an alkyl group,as defined herein, to which is attached at lease one cycloalkenyl group.

The term “cycloalkyl,” as used herein, refers to a monovalent saturatedcyclic hydrocarbon group of three to twelve carbon atoms.

The term “cycloalkylalkyl,” as used herein, refers to an alkyl group, asdefined herein, to which is attached at lease one cycloalkyl group.

The term “halo,” as used herein, refers to —F, —Cl, —Br or —I.

The term “heteroaryl,” as used herein, refers to a cyclic aromatic grouphaving five or six ring atoms, wherein at least one ring atom isselected from the group consisting of oxygen, sulfur, and nitrogen, andthe remaining ring atoms are carbon. The nitrogen atoms can beoptionally quaternized, and the sulfur atoms can be optionally oxidized.Heteroaryl groups of this invention include those derived from furan,imidazole, isothiazole, isoxazole, oxadiazole, oxazole,1,2,3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrroline, thiazole, 1,3,4-thiadiazole, thiene, triazole, and tetrazole.

The term “heteroaryl,” as used herein, also includes bicyclic ortricyclic rings, wherein any of the aforementioned heteroaryl rings isfused to one or two rings independently selected from the groupconsisting of an aryl ring, a cycloalkyl ring, a cycloalkenyl ring, andanother monocyclic heteroaryl or heterocyaloalkyl ring. These bicyclicor tricyclic heteroaryls include those derived from benzo[b]furan,benzo[b]thiene, benzimidazole, cinnoline, imidazo[4,5-c]pyridine,quinazoline, thieno[2,3-c]pyridine, thieno[3,2-b]pyridine,thieno[2,3-b]pyridine, indolizine, imidazo[1,2-a]pyridine, quinoline,isoquinoline, phthalazine, quinoxaline, naphthyridine, quinolizine,indole, isoindole, indazole, indoline, benzoxazole, benzopyrazole,benzothiozole, imidazo[1,5-a]pyridine, pyrazolo[1,5-a]pyridine,imidazo[1,2-a]pyrimidine, imidazo[1,2-c]pyrimidine,imidazo[1,5-a]pyrimidine, imidazo[1,5-c]pyrimidine,pyrrolo[2,3-b]pyridine, pyrrolo[2.3-c]pyridine, pyrrolo[3,2-c]pyridine,pyrrolo[3,2-b]pyridine, pyrrolo[2,3-d]pyrimidine,pyrrolo[3,2-d]pyrimidine, pyrrolo[2,3-b]pyrazine,pyrazolo[1,5-a]pyridine, pyrrolo[1,2-b]pyridazine,pyrrolo[1,2-c]pyrimidine, pyrrolo[1,2-a]pyrimidine,pyrrolo[1,2-a]pyrazine, triazo[1,5-a]pyridine, pteridine, purine,carbazole, acridine, phenazine, phenothiazine, phenoxazine,1,2-dihydropyrrolo[3,2,1-hi]indole, indolizine, imidazo[1,2-a]pyridine,imidazo[1,5-a]pyridine, imidazo[1,2-a]pyridine, pyrido[1,2-a]indole,10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine,5,11-dihydrodibenzo[b,e][1,4]oxazepine, and 2(1H)-pyridinone. Thebicyclic or tricyclic heteroaryl rings and can be attached to the parentmolecular group through either the heretoaryl group itself or the aryl,cycloalkyl, cycloalkenyl, or heterocycloalkyl group to which it isfused.

The term “heteroaryl,” as used herein, also includes compounds havingformula

wherein W* is —O— or —NR¹⁰—, wherein R¹⁰ is defined above, Y* is —C(O)—or —(C(R¹⁰)(R¹¹))_(v)—, wherein R¹⁰ and R¹¹ are defined above, and v is1, 2, or 3, and Z* is —CH₂—, —O—, —CH₂S(O)_(t)—, wherein t is zero, oneor two, —CH₂O—, —CH₂NR¹⁰—, or —NR¹⁰—, wherein R¹⁰ is defined above. Theheteroaryl groups of this invention can be optionally substituted.

The term “heteroaryloxy,” as used herein, refers to a heteroaryl groupattached to the parent molecular group through an oxygen atom. Theheteroaryloxy groups of this invention can be optionally substituted.

The term “heterocycloalkyl,” as used herein, refers to a non-aromaticfive-, six- or seven-membered ring having between one and threeheteroatoms independently selected from oxygen, sulfur, and nitrogen,wherein each 5-membered ring has zero to one double bonds and eachsix-membered ring has zero to 2 double bonds. Representativeheterocycloalkyl groups include 3,4-dihydropyridinyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, tetrahydrofuryl, and1,2,3,4-tetrahydropyridinyl. The heterocycloalkyl groups of thisinvention can be optionally substituted.

The term “heterocycloalkyloyl,” as used herein, refers to aheterocycloalkyl group attached to the parent molecular moiety through acarbonyl group.

The term “hydroxy,” as used herein, refers to —OH.

The term “imine,” as used herein, refers to —C(═NR²¹)—, wherein R²¹ isdefined above.

The term “nitro,” as used herein, refers to —NO₂.

The term “nitrogen-protecting group,” as used herein, refers to groupsintended to protect an amino group against undesirable reactions duringsynthetic procedures. Commonly used nitrogen-protecting groups aredisclosed in Greene, “Protective Groups In Organic Synthesis,” (JohnWiley & Sons, New York (1991)). Common N-protecting groups comprise (a)acyl groups such as formyl, acetyl, propionyl, pivaloyl,tert-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl,trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl,benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, and 4-nitrobenzoyl, (b)sulfonyl groups such as benzenesulfonyl, and para-toluenesulfonyl, (c)carbamate forming groups such as benzyloxycarbonyl,para-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl,tert-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl,cyclohexyloxycarbonyl, and phenylthiocarbonyl, (d) arylalkyl groups suchas benzyl, triphenylmethyl, and benzyloxymethyl, and (e) silyl groupssuch as trimethylsily. Preferred N-protecting groups are formyl, acetyl,benzoyl, pivaloyl, tert-butylacetyl, phenylsulfonyl, benzyl,tert-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

The term “oxo,” as used herein, refers to (═O).

The term “perfluoroalkyl,” as used herein, refers to an alkyl group inwhich all of the hydrogen atoms have been replaced by fluorine atoms.

The term “perfluoroalkoxy,” as used herein, refers to a perfluoroalkylgroup attached to the parent molecular group through an oxygen atom.

The term “perfluoroalkyl,” as used herein, refers to an alkyl group inwhich all of the hydrogen atoms have been replaced by fluoride atoms.

The term “pharmaceutically acceptable salt,” as used herein, refers tosalts which are, within the scope of sound medical judgment, suitablefor use in contact with the tissues of humans and lower animals withoutundue toxicity, irritation, or allergic response and are commensuratewith a reasonable benefit/risk ratio. Pharmaceutically acceptable saltsare well-known in the art. For example, S. M. Berge, et al. describepharmaceutically acceptable salts in detail in J. PharmaceuticalSciences, 1977, 66: 1 et seq, hereby incorporated by reference. Thesalts may be prepared in situ during the final isolation andpurification of the compounds of the invention or separately by reactinga free base function with a suitable acid. Representative acid additionsalts include acetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate,digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethansulfonate (isethionate), lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, phosphate, glutamate,bicarbonate, p-toluenesulfonate and undecanoate. Also, the basicnitrogen-containing groups can be quaternized with such agents as loweralkyl halides such as methyl, ethyl, propyl, and butyl chlorides,bromides and iodides; dialkyl sulfates such as dimethyl, diethyl,dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl,myristyl, and stearyl chlorides, bromides and iodides; and arylalkylhalides such as benzyl and phenethyl bromides. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which maybe employed to form pharmaceutically acceptable acid addition saltsinclude such inorganic acids as hydrochloric acid, hydrobromic acid,sulphuric acid and phosphoric acid and such organic acids as oxalicacid, maleic acid, succinic acid, and citric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as the hydroxide,carbonate or bicarbonate of a pharmaceutically acceptable metal cationor with ammonia or an organic primary, secondary or tertiary amine.Pharmaceutically acceptable salts include, but are not limited to,cations based on alkali metals or alkaline earth metals such as lithium,sodium, potassium, calcium, magnesium and aluminum salts and the likeand nontoxic quaternary ammonia and amine cations including ammonium,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, triethylamine, diethylamine, and ethylamine. Otherrepresentative organic amines useful for the formation of base additionsalts include ethylenediamine, ethanolamine, diethanolamine, piperidine,and piperazine.

The term “pharmaceutically acceptable prodrugs,” as used herein refersto, those prodrugs of the compounds of the present invention which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals with undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of theinvention.

The term “prodrug,” as used herein, represents compounds which arerapidly transformed in vivo to parent compounds having formula (I), forexample, by hydrolysis in blood. A thorough discussion is provided in T.Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 ofthe A.C.S. Symposium Series, and in Edward B. Roche, ed., BioreversibleCarriers in Drug Design, American Pharmaceutical Association andPergamon Press, 1987, both of which are hereby incorporated byreference. Particularly preferred prodrugs of the invention includecompounds having formula (I), wherein a nitrogen, hydroxy, or thiolgroup has attached thereto an aminoacyl, bisaminoacyl (2-mer), ortrisaminoacyl (3-mer) group optionally capped with a carboxyl protectinggroup. The term “aminoacyl,” as used herein, refers to a group derivedfrom naturally or unnaturally occuring amino acids. Representativeaminoacyl groups include those derived from glycine, alanine, β-alanine,valine, leucine, iso-leucine, methionine, serine, threonine, cysteine,phenylalanine, and tyrosine in the racemic, D or L configurations. Theaminoacyl groups of this invention can be optionally substituted. Theterms “bisaminoacyl” and “trisaminoacyl,” as used herein, refer todi-and tri-aminoacyl groups, respectively. Representative examples ofbisaminoacyl and trisaminoacyl groups include 2-mers and 3-mers derivedfrom glycine, alanine, β-alanine, valine, leucine, iso-leucine,methionine, serine, threonine, cysteine, phenylalanine, and tyrosine inthe racemic, D or L configurations.

The term “thioalkoxy,” as used herein, refers to an alkyl group attachedto the parent molecular group through a sulfur atom.

The present invention contemplates metabolites formed by in vivobiotransformation of compounds having formula (I). The term“metabolite,” as used herein, refers to compounds formed by in vivobiotransformation of compounds having formula (I) by oxidation,reduction, hydrolysis, or conjugation. The present invention alsocontemplates compounds which undergo in vivo biotransformation such asby oxidation, reduction, hydrolysis, or conjugation to form compoundshaving formula (I). A thorough discussion of biotransformation isprovided in Goodman and Gilman's, The Pharmacological Basis ofTherapeutics, seventh edition, hereby incorporated by reference.

Asymmetric or chiral centers may exist in the compounds of the presentinvention. The present invention contemplates the various stereoisomersand mixtures thereof. Individual stereoisomers of compounds of thepresent invention are prepared synthetically from commercially availablestarting materials which contain asymmetric or chiral centers or bypreparation of mixtures of enantiomeric compounds followed by resolutionwell-known to those of ordinary skill in the art. These methods ofresolution are exemplified by (1) attachment of a racemic mixture ofenantiomers to a chiral auxiliary, separation of the resultingdiastereomers by recrystallization or chromatography and liberation ofthe optically pure product from the auxiliary or (2) direct separationof the mixture of optical enantiomers on chiral chromatographic columns.

Geometric isomers may also exist in the compounds of the presentinvention. The present invention contemplates the various geometricisomers and mixtures thereof resulting from the arrangement ofsubstituents around a carbon-carbon double bond.

Compounds falling within the scope of formula (I) include, but are notlimited to

4-methoxy-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,

3,4-dimethoxy-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,

4-trifluoromethoxy-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,

4-trifluoromethyl-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,

4-nitro-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,

4-amino-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,

4-((2-chloroacetyl)amino)-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,

2-nitro-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,

4-methoxy-3-nitro-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,

3-amino-4-methoxy-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,

1-formyl-N-(3,4,5-trimethoxyphenyl)indoline-5-sulfonamide,

N-(3,4,5-trimethoxyphenyl)indoline-5-sulfonamide,

5-nitro-N-(3,4,5-trimethoxyphenyl)-1H-indole-3-sulfonamide,

1-methyl-N-(3,4,5-trimethoxyphenyl)indoline-5-sulfonamide,

1-methyl-5-nitro-N-(3,4,5-trimethoxyphenyl)-1H-indole-3-sulfonamide,

5-amino-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-3-sulfonamide,

5-amino-N-(3,4,5-trimethoxyphenyl)-1H-indole-3-sulfonamide,

N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,

1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,

N,1-dimethyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,

3,4,5-trimethoxy-N-(4-methoxyphenyl)benzenesulfonamide,

N-(3-hydroxy-4-methoxyphenyl)-3,4,5-trimethoxybenzenesulfonamide,

N-(1-methyl-1H-indol-5-yl)-3,4,5-trimethoxybenzenesulfonamide,

N-(4-(dimethylamino)phenyl)-3,4,5-trimethoxybenzenesulfonamide,

N-(4-fluoro-3-methoxyphenyl)-3,4,5-trimethoxybenzenesulfonamide,

3,4,5-trimethoxy-N-(4-(trifluoromethoxy)phenyl)benzenesulfonamide,

3,4,5-trimethoxy-N-(2,3,4,5,6-pentafluorophenyl)benzenesulfonamide,

N-(3-amino-4-methoxyphenyl)-3,4,5-trimethoxybenzenesulfonamide,

3,4,5-trimethoxy-N-(1-methyl-1H-indol-4-yl)benzenesulfonamide,

3,4,5-trimethoxy-N-(1-methyl-1H-indol-6-yl)benzenesulfonamide,

N-(1H-indol-5-yl)-3,4,5-trimethoxybenzenesulfonamide,

N-(1,2-dimethyl-1H-indol-5-yl)-3,4,5-trimethoxybenzenesulfonamide,

N-(3-chloro-1H-indol-5-yl)-3,4,5-trimethoxybenzenesulfonamide,

N-(1H-indazol-5-yl)-3,4,5-trimethoxybenzenesulfonamide,

3,4,5-trimethoxy-N-(1-methyl-1H-benzimidazol-6-yl)benzenesulfonamide,

3,4,5-trimethoxy-N-(1-methyl-1H-benzimidazol-5-yl)benzenesulfonamide,

3,4,5-trimethoxy-N-methyl-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,

3,4,5-trimethoxy-N-(2-(dimethylamino)ethyl)-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,

1H-indol-5-yl 3,4,5-trimethoxybenzenesulfonate,

(3,4,5-trimethoxyphenyl) 4-methoxybenzenesulfonate,

3,4,5-trimethoxyphenyl) 4-methylbenzenesulfonate,

1H-indol-5-yl 3,4,5-trimethoxybenzenesulfonate,

3,4,5-trimethoxyphenyl) 3-amino-4-methoxybenzenesulfonate,

(3,4,5-trimethoxyphenyl)-4-(dimethylamino)benzenesulfonate,

4-methylphenyl 3,4,5-trimethoxybenzenesulfonate, 3,4,5-trimethoxyphenyl1-methyl-5-indolinesulfonate, and

4-methoxyphenyl 3,4,5-trimethoxybenzenesulfonate.

tert-butyl2-((1-methyl-1H-indol-5-yl)((3,4,5-trimethoxyphenyl)sulfonyl)amino)ethylcarbamate,

N-(2-hydroxyethyl)-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,

N-(2,3-dihydro-1,4-benzodioxin-6-yl)-3,4,5-trimethoxybenzenesulfonamide,

N-(2-aminoethyl)-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,

3-amino-4-methoxy-N-methyl-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,

1-ethyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,

N-acetyl-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,

3,4,5-trimethoxy-N-(6-quinolinyl)benzenesulfonamide,

N-(2-hydroxyethyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,

N-(2-fluoroethyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,

N-ethyl-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,

4-nitrophenyl-3,4,5-trimethoxybenzenesulfonate,

4-aminophenyl-3,4,5-trimethoxybenzenesulfonate,

4-dimethylaminophenyl-3,4,5-trimethoxybenzenesulfonate,

3,4,5-trimethoxyphenyl 6-methoxy-3-pyridinesulfonate,

1-methyl-2-oxo-1,2-dihydro-4-pyridinyl 3,4,5-trimethoxybenzenesulfonate.

3,4,5-trimethoxyphenyl3-((3-aminopropanoyl)amino)-4-methoxybenzenesulfonate,

3,4,5-trimethoxyphenyl3-(((2R)-2-aminopropanoyl)amino)-4-methoxybenzenesulfonate,

3,4,5-trimethoxyphenyl3-(((2R)-2-amino-3-methylbutanoyl)amino)-4-methoxybenzenesulfonate,

N-((dimethylamino)acetyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,

1-methyl-N-(((2S)-1-methylpyrrolidinyl)carbonyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,

N-((2S)-2-(dimethylamino)-3-methylbutanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,

N-((2S)-2-amino-3-methylbutanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,

1-methyl-N-((2S)-2-methylamino)propanoyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,

N-((2S)-2-amino-2-phenylethanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,

N-((2S)-2-amino-3-phenylpropanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,

1-methyl-N-((2S)-pyrrolidinylcarbonyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,

N-((2S)-2,6-diaminohexanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,

N-((2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,

(2S)-2-amino-4-oxo-4-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)butanoicacid,

(3S)-3-amino-4-oxo-4-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)butanoicacid,

(2S)-2-amino-5-oxo-5-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)pentanoicacid,

(4S)-4-amino-5-oxo-5-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)pentanoicacid,

N-((bis(2-methoxyethyl)amino)acetyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,

1-methyl-N-(4-morpholinylacetyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,

1-methyl-N-((4-methyl-1-piperazinyl)acetyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,

N-(4-(aminomethyl)benzoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,

1,2,3-trimethoxy-5-((4-methoxybenzyl)sulfanyl)benzene,

1,2,3-trimethoxy-5-((4-methoxybenzyl)sulfinyl)benzene,

1,2,3-trimethoxy-5-((4-methoxybenzyl)sulfonyl)benzene,

1,2,3-trimethoxy-5-((1-(4-methoxyphenyl)-1-methylethyl)sulfonyl)benzene,

2-methoxy-5-(((3,4,5-trimethoxyphenyl)sulfanyl)methyl)aniline,

2-methoxy-5-(((3,4,5-trimethoxyphenyl)sulfinyl)methyl)aniline,2-methoxy-5-(((3,4,5-trimethoxyphenyl)sulfonyl)methyl)aniline,

2-methoxy-5-(1-methyl-1-((3,4,5-trimethoxyphenyl)sulfonyl)ethyl)aniline,

1,2,3-trimethoxy-5-(((4-methoxyphenyl)sulfanyl)methyl)benzene,

1,2,3-trimethoxy-5-(((4-methoxyphenyl)sulfonyl)methyl)benzene,

1,2,3-trimethoxy-5-(1-((4-methoxyphenyl)sulfonyl)-1-methylethyl)benzene,

2-methoxy-5-((3,4,5-trimethoxybenzyl)sulfonyl)aniline,

2-methoxy-5-((1-methyl-1-(3,4,5-trimethoxyphenyl)ethyl)sulfonyl)aniline,

1,2,3-trimethoxy-5-((phenylsulfonyl)methyl)benzene,

N-(2-aminoacetyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,

N-(2-aminoacetyl)-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,

N-((2S)-2-aminopropanoyl]-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,

N-((2S)-2-aminopropanoyl]-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,

N-(3-aminopropanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,

N-(3-aminopropanoyl)-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,

(2S)-2-amino-N-((1S)-1-methyl-2-oxo-2-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)ethyl)propanamide,

(2S)-2-amino-N-((1S)-1-methyl-2-((1-methyl-1H-indol-5-yl)((3,4,5-trimethoxyphenyl)sulfonyl)amino)-2-oxoethyl)propanamide,

N-((2S)-2-amino-3-hydroxypropanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,and

N-((2S)-2-amino-3-hydroxypropanoyl)-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide.

A more preferred compound for the practice of the present invention is

N-((dimethylamino)acetyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide.

Determination of Biological Activity

Compounds of this invention were tested in a 48-hour cellularproliferation assay which uses human colon adenocarcinoma, MDR positive(HCT-15) cells, and human lung large cell carcinoma, MDR negative(NCI-H460) cells, in the 96-well microtitre format described in SkehanP., et al. New Colorimetric Cytotoxicity Assay for Anticancer DrugScreening. 1990, J. Natl. Cancer Inst. 82:1107-1112, hereby incorporatedby reference. Briefly, the wells of a microtitre plate were chargedsequentially with cultured cells and compounds of the invention(1.0×10⁻⁴ to 1.0×10⁻¹¹ M in 10% DMSO prepared by dissolving compounds ofthe invention in DMSO and adding 11 μL of the DMSO solution to 100 μL ofculture medium for a final DMSO concentration of 10%). Two of thefollowing controls were also present in each microtitre plate: a solvent(DMSO) control without drug that yielded a 0% inhibition level and atrichloroacetic acid-treated well that yielded a 100% inhibition level.The cells were grown in culture (37° C., 5% CO₂ atmosphere) for 48 hoursthen fixed by the addition of trichloroacetic acid. The wells werestained with sulforhodamine, washed with 1% acetic acid, and treatedwith 0.01M tris buffer (100 μL) to solubilize the adherent dye. Theabsorbance of the dye solution was measured with a Molecular DevicesSpectraMax340 plate reader. The percent inhibition values were obtainedby calculating the proportional response of the experimental values tothe absorbance values of the controls. The results for representativeexamples of compounds having formula (I) are shown in Table 1. TABLE 1Inhibitory Potency of Representative Compounds NCI-460 HCT-15 %inhibition at % inhibition at Example 10⁻⁴ M 10⁻⁴ M 1 98.5 99.4 299.6 >95 3 100.0 94.4 4 99.8 82.6 5 99.9 68.5 6 >95 54.8 7 89.2 96.7 850.0 53.8 9 47.4 77.2 10 99.6 99.8 11 74.0 79.9 12 59.3 86.2 13 41.715.9 14 96.1 97.6 15 45.5 50.6 16 87.0 91.9 17 <9.1 37.0 18 89.1 94.1 19100.0 100.0 20 99.9 100.0 21 96.0 97.8 22 99.5 99.8 23 100.0 100.0 2492.0 95.8 25 57.8 62.1 26 46.7 70.9 27 61.6 57.0 28 99.8 99.9 29 90.895.1 30 83.8 94.9 31 95.1 98.6 32 99.8 99.8 33 2.8 92.0 34 18.5 47.6 3534.5 65.2 36 99.5 99.3 37 100.0 99.9 38 81.0 87.5 39 100.0 100.0 40 99.999.9 41 99.5 99.8 42 100.0 100.0 43 100.0 100.0 44 99.9 100.0 45 99.499.9 46 99.5 99.6 47 99.9 100.0 85 99.6 99.8 86 96.5 99.4 87 99.6 99.988 58.4 85.5 89 99.9 99.9 90 99.8 99.5 91 99.8 95.0 92 9.1 67.1 93 98.699.9 94 90.1 97.7 95 9.1 84.8 96 99.9 99.8

As shown by the data in Table 1, the compounds of the invention,including, but not limited to those specified in the examples, areuseful for the treatment of disease caused or exascerbated by cellproliferation. As cell proliferation inhibitors, these compounds areuseful in the treatment of both primary and metastatic solid tumors andcarcinomas of the breast, colon, rectum, lung, oropharynx, hypopharynx,esophagus, stomach, pancreas, liver, gallbladder, bile ducts, smallintestine, urinary tract including kidney, bladder and urothelium,female genital tract including cervix, uterus, ovaries, choriocarcinoma,and gestational trophoblastic disease, male genital tract includingprostate, seminal vesicles, testes, and germ cell tumors, endocrineglands including thyroid, adrenal, and pituitary, skin includinghemangiomas, melanomas, sarcomas arising from bone or soft tissuesincluding Kaposi's sarcoma, tumors of the brain, nerves, and eyes,meninges including astrocytomas, gliomas, glioblastomas,retinoblastomas, neuromas, neuroblastomas, Schwannomas and meningiomas,solid tumors arising from hematopoietic malignancies including leukemiasand chloromas, plasmacytomas, plaques, tumors of mycosis fungoides,cutaneous T-cell lymphoma/leukemia, lymphomas including Hodgkin's andnon-Hodgkin's lymphomas, prophylaxis of autoimmune diseases includingrheumatoid, immune and degenerative arthritis, ocular diseases includingdiabetic retinopathy, retinopathy of prematurity, corneal graftrejection, retrolental fibroplasia, neovascular glaucoma, rubeosis,retinal neovascularization due to macular degeneration, hypoxia,abnormal neovascularization conditions of the eye, skin diseasesincluding psoriasis, blood vessel diseases including hemagiomas andcapillary proliferation within atherosclerotic plaques, Osler-WebberSyndrome, myocardial angiogenesis, plaque neovascularization,telangiectasia, hemophiliac joints, angiofibroma, and wound granulation.

The compounds of the present invention may also be useful for theprevention of metastases from the tumors described above either whenused alone or in combination with radiotherapy and/or otherchemotherapeutic treatments conventionally administered to patients fortreating cancer. For example, when used in the treatment of solidtumors, compounds of the present invention may be administered withchemotherapeutic agents such as alpha inteferon, COMP (cyclophosphamide,vincristine, methotrexate, and prednisone), etoposide, mBACOD(methortrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine,and dexamethasone), PRO-MACE/MOPP (prednisone, methotrexate (w/leucovinrescue), doxorubicin, cyclophosphamide, paclitaxel,etoposide/mechlorethamine, vincristine, prednisone, and procarbazine),vincristine, vinblastine, angioinhibins, TNP-470, pentosan polysulfate,platelet factor 4, angiostatin, LM-609, SU-101, CM-101, Techgalan,thalidomide, SP-PG, and the like. Other chemotherapeutic agents includealkylating agents such as nitrogen mustards (mechloethamine, melphan,chlorambucil, cyclophosphamide and ifosfamide), nitrosoureas includingcarmustine, lomustine, semustine and streptozocin, alkyl sulfonatesincluding busulfan, triazines including dacarbazine, ethyeniminesincluding thiotepa and hexamethylmelamine, folic acid analogs includingmethotrexate, pyrimidine analogues including 5-fluorouracil and cytosinearabinoside, purine analogs including 6-mercaptopurine and6-thioguanine, antitumor antibiotics including actinomycin D,anthracyclines including doxorubicin, bleomycin, mitomycin C andmethramycin, hormones and hormone antagonists including tamoxifen,cortiosteroids and miscellaneous agents including cisplatin andbrequinar. For example, a tumor may be treated conventionally withsurgery, radiation, or chemotherapy, and compounds having formula (I),then treated with additional compound having formula (I) to extend thedormancy of micrometastases and to stabilize and inhibit the growth ofany residual primary tumor.

Methods of Treatment

The present invention also provides pharmaceutical compositions whichcomprise compounds of the present invention formulated together with oneor more non-toxic pharmaceutically acceptable carriers. Thepharmaceutical compositions may be specially formulated for oraladministration in solid or liquid form, for parenteral injection, or forrectal administration.

The pharmaceutical compositions of this invention can be administered tohumans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, or as an oral or nasal spray.The term “parenteral” administration as used herein refers to modes ofadministration which include intravenous, intramuscular,intraperitoneal, intrasternal, subcutaneous and intraarticular injectionand infusion.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions as well as sterilepowders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol, and the like), and suitable mixtures thereof, vegetable oils(such as olive oil), and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservative,wetting agents, emulsifying agents, and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents such as sugars, sodium chloride,and the like, Prolonged absorption of the injectable pharmaceutical formmay be brought about by the inclusion of agents which delay absorptionsuch as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides) Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan, andmixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, and tragacanth, and mixturesthereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono-or multi-lamellar hydrated liquid crystals that are dispersed in anaqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thecompositions in liposome form can contain, in addition to a compound ofthe present invention, stabilizers, preservatives, excipients, and thelike. The preferred lipids are the phospholipids and the phosphatidylcholines (lecithins), both natural and synthetic.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compound ismixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers, or propellants which maybe required. Opthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention. Actual dosage levels of active ingredients in thepharmaceutical compositions of this invention may be varied so as toobtain an amount of the active compound(s) that is effective to achievethe desired therapeutic response for a particular patient, compositions,and mode of administration. The selected dosage level will depend uponthe activity of the particular compound, the route of administration,the severity of the condition being treated, and the condition and priormedical history of the patient being treated. However, it is within theskill of the art to start doses of the compound at levels lower thanrequired for to achieve the desired therapeutic effect and to graduallyincrease the dosage until the desired effect is achieved.

Generally dosage levels of about 1 to about 50, more preferably of about5 to about 20 mg of active compound per kilogram of body weight per dayare administered orally to a mammalian patient. If desired, theeffective daily dose may be divided into multiple doses for purposes ofadministration, e.g. two to four separate doses per day.

Synthetic Methods

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes, whichillustrate methods by which the compounds of the invention may beprepared. The compounds having formula (I) may be prepared by a varietyof synthetic routes. Representative procedures are shown in Scheme 1.The groups R¹, R², R³, R⁴, R⁵, R⁶, R¹², R¹³, and L¹, are as previouslydefined unless otherwise noted. It will be readily apparent to one ofordinary skill in the art that other compounds within formula (I) can besynthesized by substitution of the appropriate reactants and agents inthe syntheses shown below. It will further be apparent to one skilled inthe art that the selective protection and deprotection steps, as well asorder of the steps themselves, can be carried out in varying order,depending on the nature of groups R¹, R², R³, R⁴, R⁵, R⁶, R¹², R¹³, andL¹, to successfully complete the syntheses of compounds having formula(I). Commonly used protecting groups are disclosed in Greene,“Protective Groups In Organic Synthesis,” John Wiley & Sons, New York(1981), hereby incorporated by reference. It will still further beapparent to one of ordinary skill in the art that the substituents R¹,R², R³, R⁴, R⁵, R⁶, R¹², R¹³, and L¹, can be determined by selection ofthe appropriate commercially available or known starting materials orintroduced synthetically by known chemical methods such as thosedisclosed in Larock, “Comprehensive Organic Transformations. A Guide toFunctional Group Preparations,” VCH Publishers, New York (1989), herebyincorporated by reference.

Abbreviations

Abbreviations used in the descriptions of the schemes the examples are:THF for tetrahydrofuran; DMF for N,N-dimethylformamide; DMSO fordimethylsulfoxide; DEAD for diethyl azodicarboxylate; DIAD fordiisopropyl azodicarboxylate; EDC for1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; LDA forlithium diisopropylamide; TFA for trifluoroacetic acid; DMSO fordimethylsulfoxide; DMAP for 4-(N,N-dimethylamino)pyridine; HATU forO-(azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate;Boc for tert-butylcarbonyloxy; DPPA for diphenylphosphoryl azide; DCCfor dicyclohexylcarbodiimide; HOOBT for3-hydroxy-1,2,3-benzotriazin-4(3H)-one; HOBT for 1-hydroxybenzotriazolehydrate; EDCI for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride; CDI for 1,1′-carbonyldiimidazole; and DMAP forN,N-dimethylaminopyridine.

As shown in Scheme 1, the compounds having formula (I) were prepared byreacting intermediate (i) with intermediate (ii), wherein X¹ and X²together are L¹. With either (i) or (ii), X¹ or X² can be anyconventional activated sulfonic acid, examples of which include sulfonylhalides, sulfonic acid anhydrides, and N-sulfonylimidazolides,preferably sulfonyl halides. Although the solvent used in the couplingreactions is not particularly limited, a solvent in which the startingmaterials are both soluble and which is little reactive with thematerials is preferably used. Examples of such solvents are pyridine,triethylamine, THF, dioxane, benzene, toluene, diethyl ether,dichloromethane, DMF, DMSO, or mixtures thereof. When an acid isliberated with the progress of a reaction, such as when using a halidederivative of a sulfonic acid and an amine or alcohol, it is preferablethat the reaction is carried out in the presence of a suitabledeacidifying agent. For this reason, the use of a basic solvent such aspyridine or triethylamine is particularly preferred, although thereaction can be run in any of the aforementioned solvents with at leasta stoichiometric amount of basic solvent present. Although the reactionsgenerally proceed at room temperature, they can be run at lower orelevated temperatures, as needed. The reaction time is generally 30minutes to 18 hours and can be arbitrarily selected depending on thetypes of starting materials and reaction temperature. When the producthas a protected amino or hydroxyl group, the product, if necessary, canbe converted to a compound having formula (I) having a free amino orhydroxyl group by a conventional deprotection method such as treatmentwith acid, piperidine, or catalytic hydrogenation in the presence of acatalyst such as palladium on carbon. When the compound having formula(D has a nitro group, the nitro group can also be reduced. Although thereduction can be conducted by any conventional process, the conversionof a nitro group to an amine is preferably conducted by catalytichydrogenation using palladium on carbon or platinum oxide as thecatalyst or reduction using an acid together with zinc, iron, or tin.The catalytic reduction is conducted in an organic solvent such asmethanol, ethanol, or THF under normal or elevated temperature. Groupson the compounds having formula (I) having endogenous or exogenous aminogroups can optionally alkylated, formylated, acetylated or otherwisereacted with any number of amine-derivatization reagents well-known tothose of ordinary skill in the art. For example, acidic N—H groups canbe reacted with alcohols under Mitsunobu conditions. PreferableMitsunobu conditions include reacting the compounds having formula (I)with alcohols in the presence of a phosphine, preferablytriphenylphosphine or tri n-butylphosphine and an activating agent suchas DEAD or DIAD. Although the solvent to be used in the reaction is notparticularly limited, polar, aprotic solvents such as THF or dioxane areparticularly preferable for Mitsunobu reactions. The compounds havingformula (I) can also be alkylated with any number of reagents well-knownto those of ordinary skill in the art. For example, compounds havingformula (I) can be reacted with an unsubstituted or substitutedalkylating agent in the presence of a non-nucleophilic base such assodium or potassium hydride or lithium, sodium, or potassiumbis(trimethylsilyl)amide. Although the solvent to be used in thereaction is not particularly limited, polar, aprotic solvents such asTHF, DMF, DMSO, or dioxane are particularly preferable for alkylationreactions. Compounds having formula (I) can be reacted with halogenationagents. Examples of halogenating agents include N-chlorosuccinamide,N-bromosuccinamide, 1,3-bibromo-5,5-dimethylhydantoin, N-bromoacetamide,bromine, chlorine, or iodine. Although the solvent to be used in thereaction is not particularly limited, chloroalkanes such asdichloromethane, chloroform, or carbon tetrachloride, halogenatedaromatic rings such as chlorobenzene and dichlorobenzene, water, ororganic acids, such as acetic acid, are particularly preferable.

As shown in Scheme 2, compounds of formula (I) (R⁷ is H) can beintraconverted to compounds of formula (I) (R⁷is an aminoacyl,bisaminoacyl (2-mer), or trisaminoacyl (3-mer) residue optionally cappedwith a carboxyl protecting group) by reaction with naturally orunnaturally occurring amino acids or with 2-mers and 3-mers derived fromamino acids. Representative amino acids include N,N-dimethylglycine,N-methyl-L-proline, N,N-dimethyl-L-valine,N-tert-butoxycarbonyl)-L-valine,N-(tert-butoxy-carbonyl)-L-N-methylalanine,(S)-N-(tert-butoxycarbonyl)-2-phenylglycine,N-(tert-butoxycarbonyl)-L-phenylalanine,N-(tert-butoxycarbonyl)-L-proline,N,N-di-(tert-butoxycarbonyl)-L-lysine, N-(tert-butoxycarbonyl)-L-valine,N-(tert-butoxycarbonyl)-L-aspartic acid 1-tert-butyl ester,N-(tert-butoxycarbonyl)-L-aspartic acid 4-tert-butyl ester,N-(tert-butoxycarbonyl)-L-glutamic acid 1-tert-butyl ester,N-(tert-butoxycarbonyl)-L-glutamic acid 5-tert-butyl ester,(bis(2-methoxyethyl)amino)acetic acid, 4-morpholinylacetic acid,(4-methyl-1-piperazinyl)acetic acid, and4-(((tert-butoxy-carbonyl)amino)methyl)benzoic acid in the presence ofbase and an activating agent. Naturally occurring amino acids can bepurchased commercially, while unnaturally occurring amino acids can besynthesized by methods well-known in the art. Representative basesinclude 4-pyrrolidinylpyridine, DMAP, and triethylamine. Examples ofactivating used in these reactions include DCC, EDCI, HOBT, and CDI.Typical solvents used in these reactions include dichloromethane, carbontetrachloride, and chloroform. The reaction temperature is about 0° C.to about 30° C. and depends on the method chosen. Reaction times aretypically about 2 to about 24 hours. In a preferred embodiment,compounds of formula (D (R is H) in dichloromethane at room temperatureare reacted with a naturally or unnaturally occurring amino acid in thepresence of DCC and 4-pyrrolidinylpyridine for 16 hours to providecompounds of formula (I) (R⁷ is an aminoacyl, bisaminoacyl (2-mer), ortrisaminoacyl (3-mer) residue optionally capped with a carboxylprotecting group).

Scheme 3 shows the method of preparation for compounds of formula (I)(L¹ is —S(O)CR¹²R¹³—, —SO₂CR¹²R¹³—, —SCR¹²R¹³—, —CR¹²R¹³S(O)—,—CR¹²R¹³SO₂—, or —CR¹²R¹³S—). Intermediates (iii) and (iv) (one of A¹and A² is —CH₂Cl; the other is SH) can be combined in the presence ofbase to provide the desired products. Examples of bases used in thesereactions include KOH, NaOH, and LiOH. Representative solvents includeN,N-dimethylformamide, dioxane, N-methylpyrrolidinone, and mixturesthereof. The reaction temperature is about 25° C. to about 50° C. andreaction times are typically about 1 to about 12 hours.

Compounds of formula (I) (L¹ is —SCR¹²R¹³— or —CR¹²R¹³S—) can beintraconverted to compounds of formula (I) (L¹ is S(O)CR¹²R¹³—,—SO₂CR¹²R¹³—, —SCR¹²R¹³—, —CR¹²R¹³S(O)—, or —CR¹²R¹³SO₂—) by treatmentwith an oxidizing agent. Representative oxidizing agents include H₂O₂with acetic anhydride, and potassium peroxymonosulfate (OXONE®).Examples of solvents used in these reactions include dichloromethane,acetone, 1,2-dichloroethane, chloroform, and mixtures thereof. Thereaction temperature is about 25° C. to about 40° C. and depends on themethod chosen. Reaction times are typically about 8 hours to about 24hours.

Compounds of formula (I) wherein L¹ is —SO₂CR¹²R¹³— or —CR¹²R¹³SO₂— (R¹²and R¹³ are hydrogen) can be intraconverted to compounds of formula (I)wherein L¹ is —SO₂CR¹²R¹³— or —CR¹²R¹³SO₂— (R¹² and R¹³ are alkyl) bytreatment with a base and an alkylating agent. Representative basesinclude lithium hexamethyldisilazide, sodium hexamethyldisilazide,potassium hexamethyldisilazide, and lithium diisopropylamide.Representative alkylating agents include iodomethane, bromopropane,iodobutane, and the like. Examples of solvents used in these reactionsinclude tetrahydrofuran, dioxane, diethyl ether, and methyl tert butylether. Reaction times are about 2 hours to about 6 hours, and reactiontemperatures are typically about 0° C. to about 30° C.

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration of, and not a limitation upon, the scope of theinvention as defined in the appended claims.

EXAMPLE 1 4-methoxy-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide

A solution of 3,4,5-trimethoxyaniline (500 mg, 2.8 mmol) in pyridine (5mL) was treated with 4-methoxybenzenesulfonyl chloride (564 mg, 2.8mmol) in THF (5 mL), stirred at room temperature for 18 hours,concentrated, redissolved in THF (1 mL), treated with water withstirring, and filtered to provide 820 mg of the desired product.

MS (DCI/NH₃) m/z 354 (M+H)⁺ and 371 (M+NH₄)⁺; ¹H NMR (300 MHz, CDCl₃) δ7.85 (d, J=7.5 Hz, 2H), 6.91 (d, J=7.5 Hz, 2H), 6.29 (s, 2H), 3.84 (s,3H), 3.78 (s, 3H), 3.75 (s, 6H).

EXAMPLE 2 3,4-dimethoxy-N-(3,4,5-trimethoxyphenyl)benzamide

3,4,5-trimethoxyaniline (232 mg) was processed as described in Example 1(substituting 3,4-dimethoxybenzenesulfonyl chloride for4-methoxybenzenesulfonyl chloride with) to provide 375 mg of the desiredproduct.

MS (DCI/NH₃) m/z 384 (M+H)⁺ and 401 (M+NH₄)⁺; ¹H NMR (300 MHz, CDCl₃) δ7.38 (dd, J=2.4, 8.4 Hz, 1H), 7.18 (d, J=2.4 Hz, 1H), 6.87 (d, J=8.4 Hz,1H), 6.30 (s, 2H), 3.92 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.76 (s,6H).

EXAMPLE 34-trifluoromethoxy-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide

3,4,5-trimethoxyaniline (200 mg) was processed as described in Example 1(substituting 4-trifluoromethoxybenzenesulfonyl chloride for4-methoxybenzenesulfonyl chloride with) to provide 330 mg of the desiredproduct.

MS (DCI/NH₃) m/z 408 (M+H)⁺ and 425 (M+NH₄)⁺; ¹H NMR (DMSO-d₆, 300 MHz)δ 10.05 (s, 1H), 7.08 (d, J=9.3 Hz, 1H), 6.98 (s, 2H), 6.86 (d, J=9.3Hz, 1H), 3.76 (s, 6H), 3.70 (s, 3H), 3.64 (s, 3H).

EXAMPLE 4 4-trifluoromethyl-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide

3,4,5-trimethoxyaniline (200 mg) was processed as described in Example 1(substituting 4-trifluoromethylbenzenesulfonyl chloride for4-methoxybenzenesulfonyl chloride with) to provide 375 mg of the desiredproduct.

MS (DCI/NH₃) m/z 392 (M+H)⁺ and 409 (M+NH₄)⁺; ¹H NMR (DMSO-d₆, 300 MHz)δ 10.35 (s, 1H), 7.98 (s, 4H), 6.37 (s, 2H), 3.65 (s, 6H), 3.57 (s, 3H).

EXAMPLE 5 4-nitro-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide

3,4,5-trimethoxyaniline (500 mg) was processed as described in Example 1(substituting 4-nitrobenzenesulfonyl chloride for4-methoxybenzenesulfonyl chloride) to provide 850 mg of the desiredproduct.

MS (DCI/NH₃) m/z 369 (M+H)⁺ and 386 (M+NH₄)⁺; ¹H NMR (DMSO-d₆, 300 MHz)δ 10.46 (s, 1H), 8.39 (d, J=8.4 Hz, 2H), 8.02 (d, J=8.4 Hz, 2H), 6.39(s, 2H), 3.66 (s, 6H), 3.56 (s, 3H).

EXAMPLE 6 4-amino-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide

A solution of Example 5 (100 mg, 0.20 mmol) in in 1:1 THF:methanol (2mL) was purged with nitrogen, treated with and 10% palladium on carbon(100 mg), stirred under hydrogen (1 atm) for 2 hours, filtered throughdiatomaceous earth (Celite®), and concentrated to provide 90 mg of thedesired product. MS (DCI/NH₃) m/z 339 (M+H)⁺ and 356 (M+NH₄)⁺; ¹H NMR(DMSO-d₆, 300 MHz) δ 9.69 (s, 1H), 7.41 (d, J=8.7 Hz, 2H), 6.54 (d,J=8.7 Hz, 2H), 6.36 (s, 2H), 5.98 (br s, 2H), 3.64 (s, 6H), 3.55 (s,3H).

EXAMPLE 74-((2-chloroacetyl)amino)-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide

A suspension of Example 6 (30 mg, 0.09 mmole) in dichloromethane (1 mL)was treated sequentially with triethylamine (19 μL) and chloroaceticanhydride (46 mg) to form a clear solution, and concentrated to providediacylated product. The diacylated product was dissolved in methanol (1mL), treated with NaHCO₃, and stirred for 18 hours. The slurry waswashed with water, dried (Na₂SO₄), filtered, and concentrated to provide15 mg of the desired product.

MS (DCI/NH₃) m/z 415 (M+H)⁺ and 437 (M+Na)⁺; ¹H NMR (DMSO-d₆, 300 MHz) δ10.67 (s, 1H), 7.74 (s, 4H), 6.36 (s, 2H), 4.28 (s, 2H), 3.64 (s, 6H),3.55 (s, 3H).

EXAMPLE 8 2-nitro-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide

3,4,5-trimethoxyaniline (413 mg) was processed as described in Example 1(substituting 2-nitrobenzenesulfonyl chloride for4-methoxybenzenesulfonyl chloride) to provide 800 mg of the desiredproduct.

MS (DCI/NH₃) m/z 369 (M+H)⁺ and 386 (M+NH₄)⁺; ¹H NMR (DMSO-d₆, 300 MHz)δ 7.95 (m, 2H), 7.50 (m, 2H), 6.41 (s, 2H), 3.67 (s, 6H), 3.57 (s, 3H).

EXAMPLE 9 4-methoxy-3-nitro-N-(3,4,5-trimethoxyphenyl)benzenesulfonamideEXAMPLE 9A 4-methoxy-3-nitrobenzenesulfonyl chloride

A solution of 4-methoxy sulfonyl chloride (2 g) in sulfuric acid (8 mL)at 0° C. was treated dropwise with nitric acid, stirred at 0° C. forabout 10 minutes, and carefully poured into a separatory funnelcontaining diethyl ether and ice. The water layer was extracted withdiethyl ether (3—), and the combined extracts were dried (Na2SO₄),filtered, and concentrated. The concentrate was dissolved intodichloromethane, washed with brine, dried (Na₂SO₄), filtered,concentrated, placed under high vacuum, and purified by flash columnchromatography on silica gel with 4:1 hexane/ethyl acetate to providethe desired product.

EXAMPLE 9B4-methoxy-3-nitro-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide

3,4,5-trimethoxyaniline (146 mg) was processed as described in example 1(substituting Example 9A for 4-methoxybenzenesulfonyl chloride) toprovide 280 mg of the desired product.

MS (DCI/NH₃) m/z 416 (M+NH₄)⁺; ¹H NMR (DMSO-d₆, 300 MHz) δ 8.26 (d,J=2.1 Hz, 1H), 7.99 (dd, J=2.1, 9 Hz, 1H), 7.53 (d, J=9 Hz, 1H), 6.39(s, 2H), 3.98 (s, 3H), 3.67 (s, 6H), 3.57 (s, 3H).

EXAMPLE 103-amino-4-methoxy-N-(3,4,5-trimethoxyphenyl)benzenesulfonamidehydrochloride

A solution of Example 9B (150 mg, 0.38 mmol) in 1:1 THF:methanol (8 mL)was treated with 10% palladium on carbon (100 mg), stirred underhydrogen (1 atm) for 1 hour, filtered through diatomaceous earth(Celite®), and concentrated. The concentrate was dissolved in methanol(0.5 mL), treated with 1M HCl in diethyl ether to form a white solid,treated with additional diethyl ether to cause the salt to fullyprecipitate, and filtered. The hydroscopic salt was dissolved in water(2 mL) and lyophilized to provide 100 mg of the desired product.

MS (DCI/NH₃) m/z 369 (M+H)⁺ 386 (M+NH₄)⁺;

1H NMR (DMSO-d₆, 300 MHz) δ 9.85 (s, 1H), 7.05 (d, J=2.4 Hz, 1H), 6.98(dd, J=2.4, 8.1 Hz, 1H), 6.88 (d, J=8.1 Hz, 1H), 6.38 (s, 2H), 5.19 (s,1H), 3.80 (s, 3H), 3.65 (s, 6H), 3.55 (s, 3H).

EXAMPLE 11 1-formyl-N-(3,4,5-trimethoxyphenyl)indoline-5-sulfonamideEXAMPLE 11A N-formylindoline

A solution of indoline (5.0 g) and 98% formic acid (3.0 g) in toluene(17 mL) was heated at reflux for 6 hours with a Dean-Stark trap, cooled,washed with water and concentrated. The resulting dark brown solid wasdissolved in methanol, concentrated to a fraction of its originalvolume, treated with 1:1 diethyl ether/hexane, and concentrated drynessto provide 5.5 g of the desired product.

EXAMPLE 11B 5-chlorosulfonylindoline-1-carboxaldehyde

Chlorosulfonic acid (4.6 mL) at 0° C. was treated portionwise with asample of example 11A (2.0 g) over 30 minutes, stirred for 5 minutes at0° C., heated at 100° C. until all bubbling ceased, carefully pouredover ice and water, stirred vigorously for 2 hours, filtered, and driedovernight in a vacuum oven to provide 2.5 g of the desired product.

EXAMPLE 11C 25 1-formyl-N-(3,4,5-trimethoxyphenyl)indoline-5-sulfonamide

3,4,5-trimethoxyaniline (2.51 g) was processed as described in example 1(substituting Example 11B for 4-methoxybenzenesulfonyl chloride) andpurified by column chromatography on silica gel with 2%methanol/dichloromethane to provide 4.8 g of the desired product.

MS (DCI/NH₃) 410 (M+NH₄)⁺; ¹H NMR (DMSO-d₆, 300 MHz) δ 9.85 (s, 1H),7.05 (d, J=2.4 Hz, 1H), 6.98 (dd, J=2.4, 8.1 Hz, 1H), 6.88 (d, J=8.1 Hz,1H), 6.38 (s, 2H), 5.19 (s, 1H), 3.80 (s, 3H), 3.65 (s, 6H), 3.55 (s,3H).

EXAMPLE 12 N-(3,4,5-trimethoxyphenyl)indoline-5-sulfonamide

A solution of Example 11C (4.8 g) in methanol (60 mL) at roomtemperature was treated with HCl gas for about 8 minutes, concentratedto dryness, and treated with ethyl acetate and water. The organic layerwas washed with saturated aqueous NaHCO₃ until the aqueous washings wereslightly basic, dried (Na₂SO₄), filtered, and concentrated to provide4.0 g of the desired product.

MS (DCI/NH₃) m/z 365 (M+H)⁺ 382 (M+NH₄)⁺; ¹H NMR (DMSO-d₆, 300 MHz) δ9.69 (s, 1H), 7.34 (m, 1H), 6.42 (m, 2H), 6.37 (s, 3H), 3.65 (s, 6H),3.53 (s, 3H), 3.50 (t, J=9 Hz, 2H), 2.94 (t, J=9 Hz, 2H).

EXAMPLE 13 5-nitro-N-(3,4,5-trimethoxyphenyl)-1H-indole-3-sulfonamideEXAMPLE 13A 5-nitro-1H-indole-3-sulfonyl chloride

A solution of chlorosulfonic acid (3 mL, 45 mmol) and Na₂SO₄ (700 mg,4.9 mmol) in dichloromethane (30 mL) was treated dropwise with asolution of 5-nitroindole (800 mg, 4.9 mmol) in dichloromethane (20 mL)over 1 hour, stirred for another 30 minutes, and decanted to provide athick brown oil. The oil was slowly treated with water (20 mL), stirredfor 10 minutes, filtered, and dried in a vacuum oven to provide 651 mgof the desired product.

EXAMPLE 13B 5-nitro-N-(3,4,5-trimethoxyphenyl)-1H-indole-3-sulfonamide

3,4,5-trimethoxyaniline (100 mg) was processed as described in Example 1(substituting Example 13A for 4-methoxybenzenesulfonyl chloride) andpurified by column chromatography on silica gel with 2%methanol/dichloromethane to provide 120 mg of the desired product.

MS (DCI/NH₃) m/z 407 (M+H)⁺ 425 (M+NH₄)⁺; ¹H NMR (DMSO-d₆, 300 MHz) δ10.15 (s, 1H), 8.71 (d, J=2.1 Hz, 1H), 8.27 (s, 1H), 8.10 (dd, J=2.1, 9Hz, 1H), 7.66 (d, J=9 Hz, 1H), 6.38 (s, 2H), 3.60 (s, 6H), 3.50 (s, 3H).

EXAMPLE 14 1-methyl-N-(3,4,5-trimethoxyphenyl)indoline-5-sulfonamide

A solution of Example 11C (300 mg, 0.77 mmol) in THF (15 mL) at roomtemperature was treated with 1M LiAlH₄ (7.7 mL, 7.7 mmol) to form asolid which later dissolved to give a cloudy yellow solution, stirredovernight at room temperature, cooled to 0° C., treated sequentiallywith water (0.3 mL), 15% NaOH (0.3 mL) and water (0.9 mL), stirred 30minutes, and filtered to remove the aluminum complex. The layerscomprising the filtrate were separated, and the organic layer wastreated with ethyl acetate (50 mL), washed with water (2×20 mL), dried(Na₂SO₄), filtered and concentrated. The concentrate was purified byflash column chromatography on silica gel with 2%methanol:dichloromethane to provide 260 mg of the desired product.

MS (DCI/NH₃) m/z 379 (M+H)⁺; ¹H NMR (DMSO-d₆, 300 MHz) δ 9.76 (s, 1H),7.45 (dd, J=2.1, 8.4 Hz, 1H), 7.34 (d, 1H), 6.46 (d, J=8.4 Hz, 1H), 6.37(s, 2H), 3.65 (s, 6H), 3.55 (s, 3H), 3.42 (t, J=8.4 Hz, 2H) 2.92 (t,J=8.4 Hz, 2H) 2.76 (s, 3H).

EXAMPLE 151-methyl-5-nitro-N-(3,4,5-trimethoxyphenyl)-1H-indole-3-sulfonamideEXAMPLE 15A 1-methyl-5-nitro-1H-indole-3-sulfonyl chloride

A solution of chlorosulfonic acid (1.9 mL, 28 mmol) and Na₂SO₄ (403 mg,2.8 mmol) in dichloromethane (17 mL) was treated with a solution of1-methyl-5-nitro-1H-indole (500 mg, 2.8 mmol) in dichloromethane (11 mL)over 1 hour, stirred for 30 minutes, and decanted to provide a thickbrown oil. The oil was slowly treated with water (20 mL), stirred for 10minutes, and filtered. The filtrate was dried in a vacuum oven toprovide 80 mg of the desired compound which was used in the next stepwithout further purification.

EXAMPLE 15B1-methyl-5-nitro-N-(3,4,5-trimethoxyphenyl)-1H-indole-3-sulfonamide

3,4,5-trimethoxyaniline (47 mg) was processed as described in example 1(substituting Example 15A for 4-methoxybenzenesulfonyl chloride) toprovide 59 mg of the desired product.

MS (DCI/NH₃) m/z 439 (M+NH₄)⁺; ¹H NMR (DMSO-d₆, 300 MHz) δ 10.20 (s,1H), 8.71 (d, J=2.1 Hz, 1H), 8.34 (s, 1H), 8.15 (dd, J=2.1, 9 Hz, 1H),7.76 (d, J=9 Hz, 1H), 6.40 (s, 2H), 3.91 (s, 3H), 3.61 (s, 6H) 3.51 (s,3H).

EXAMPLE 16 5-amino-1-methyl-N-(3,45-trimethoxyphenyl)-1H-indole-3-sulfonamide

A solution of Example 15 (50 mg, 0.12 mmole) in 1:1 methanol:THF (2 mL)was treated with 10% palladium on carbon, stirred under hydrogen (1 atm)for 2.5 hours, filtered through diatomaceous earth (Celite®),concentrated, redissolved in a small amount of methanol, treated withseveral drops of 1M HCl in diethyl ether until the solution becamecloudy and acidic, treated with additional diethyl ether until a solidprecipitated, filtered and dried in a vacuum oven to provide 35 mg ofthe desired the product.

MS (DCI/NH₃) m/z 392 (M+H)⁺ 409 (M+NH₄)⁺; ¹H NMR (DMSO-d₆, 300 MHz) δ9.88 (s, 1H), 7.82 (s, 1H), 7.20 (d, J=9 Hz, 1H), 6.98 (d, J=2.4 Hz,1H), 6.64 (dd, J=2.4, 9 Hz, 1H), 6.39 (s, 2H), 3.71 (s, 3H), 3.62 (s,6H), 3.52 (s, 3H).

EXAMPLE 17 5-amino-N-(3,4,5-trimethoxyphenyl)-1H-indole-3-sulfonamide

Example 13B (100 mg) was processed as described in Example 16 to provide80 mg of the desired product.

MS (DCI/NH₃) m/z 378 (M+H)⁺ 395 (M+NH₄)⁺; ¹H NMR (300 MHz, CDCl₃) δ 8.10(d, 1H), 7.83 (m, 1H), 7.60 (d, 1H), 7.26 (m, 1H), 6.39 (s, 2H), 3.61(s, 6H), 3.52 (s, 3H).

EXAMPLE 18 N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide

A solution of Example 12 (0.909 g) and salcomine (0.082 g) in methanol(125 mL) was treated with O₂ gas over 18 hours and concentrated. Theconcentrate was purified by flash column chromatography on silica gelwith 2% methanol/dichloromethane to provide the desired compound.

MS (DCI/NH₃) m/z 363 (M+H)⁺ 380 (M+NH₄)⁺; ¹H NMR (300 MHz, CDCl₃) δ 9.94(s, 1H), 8.07 (s, 1H), 7.52 (m, 2H), 6.61 (m, 1H), 6.39 (s, 2H), 3.61(s, 6H), 3.51 (s, 3H).

EXAMPLE 19 1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide

A solution of Example 18 (1.01 g, 2.8 mmol) in THF (100 mL) at 0° C. wastreated with sodium bis(trimethylsilyl)amide (1M in THF, 7 mL, 6.89mmol), stirred for 20 minutes, treated dropwise with CH₃I (195 μL, 3.1mmol), stirred over 18 hours while warming to room temperature, treatedwith water, and extracted with ethyl acetate. The extract was dried(Na₂SO₄), filtered and concentrated. The concentrate was purified byflash column chromatography on silica gel with 1%methanol/dichloromethane to provide 684 mg of the desired compound.

MS (DCI/NH₃) m/z 377 (M+H)⁺ 394 (M+NH₄)⁺; ¹H NMR (DMSO-d₆, 300 MHz) δ9.94 (s, 1H), 8.06 (t, 1H), 7.57 (m, 2H), 7.49 (d, J=3.3 Hz, 1H), 6.64(d, J=3.3 Hz, 1H), 6.39 (s, 1H), 3.81 (s, 3H), 3.62 (s, 6H), 3.51 (s,3H).

EXAMPLE 20N,1-dimethyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide

A solution of example Example 18 (50 mg, 0.14 mmol) in THF at 0° C. wastreated portionwise with NaH (60% dispersion in mineral oil, 26 mg, 0.70mmol), stired for 20 minutes, treated dropwise with CH₃I (52 μL, 0.84mmol), warmed to room temperature, stirred for 18 hours, treated withwater, and extracted with ethyl acetate (10 mL). The organic layer waswashed sequentially with water (5 mL) and brine (5 mL), dried (Na₂SO₄),filtered, and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 1% methanol:dichloromethane to provide48 of the desired product.

MS (DCI/NH₃) m/z 391 (M+H)⁺; ¹H NMR (DMSO-d₆, 300 MHz) δ 7.86 (d, J=1.5Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.54 (d, J=2.7 Hz, 1H), 7.32 (dd,J=1.5, 8.4 Hz, 1H), 6.65 (d, J=2.7 Hz, 1H), 6.29 (s, 2H), 3.86 (s, 3H),3.64 (s, 3H), 3.58 (s, 6H), 3.06 (s, 3H).

EXAMPLE 21 3,4,5-trimethoxy-N-(4-methoxyphenyl)benenesulfonamide EXAMPLE21A 3,4,5-trimethoxybenzenesulfonyl chloride

The procedure in J. Het. Chem. 23, 1253 (1986) was followed. A solutionof 3,4,5-trimethoxyaniline (5.0 g) in acetic acid (26 mL) and 12M HCl(47 mL) at −10-5° C. was treated slowly with a solution of NaNO₂ (2 g)in water (7 mL), stirred at −5° C. for another 30 minutes, added inportions to a cold (−5° C.) solution of CuCl₂ and SO₂ in acetic acid (35mL) and water (6 mL), stirred at −5-0° C. for 3 hours, warmed to roomtemperature overnight, poured over ice, filtered, and dried to providethe desired product.

EXAMPLE 21B 3,4,5-trimethoxy-N-(4-methoxyphenyl)benenesulfonamide

A solution of 4-methoxyaniline (139 mg, 1.1 mmol) in pyridine (2 mL) wastreated with Example 21A (300 mg, 1.1 mmol) in THF (2 mL), stirred atroom temperature for 18 hours, concentrated, redissolved in THF (1 mL),treated with water with stirring, and filtered to provide 300 mg of thedesired product.

MS (DCI/NH₃) m/z 353 (M+H)⁺ and 371 (M+NH₄)⁺; ¹H NMR (300 MHz, CDCl₃) δ6.99 (d, J=9 Hz, 1H), 6.80 (d, J=9 Hz, 1H), 6.85 (s, 2H), 3.87 (s, 3H),3.77 (s, 3H), 3.76 (s, 6H).

EXAMPLE 22 N-(3-hydroxy-4-methoxyphenyl)-3,4,5-trimethoxybenzamide

Example 21A was processed as described in Example 21B (substituting5-amino-2-methoxyphenol for 4-methoxyaniline) to provide the desiredproduct.

MS (DCI/NH₃) m/z 369 (M+H)⁺ and 387 (M+NH₄)⁺; ¹H NMR (300 MHz, CDCl₃) δ6.92 (s, 2H), 6.72 (d, J=8.7 Hz, 1H), 6.69 (d, 1H), 6.57 (dd, J=2.7, 8.7Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.78 (s, 6H).

EXAMPLE 23 N-(1-methyl-1H-indol-5-yl)-3,4,5-trimethoxybenzenesulfonamide

Example 21A (456 mg) was processed as described in Example 21B(substituting 1H-indol-5-amine for 4-methoxyaniline) to provide 480 mgof the desired product.

MS (DCI/NH₃) m/z 377 (M+H)⁺ and 394 (M+NH₄)⁺; ¹H NMR (300 MHz, CDCl₃) δ7.32 (d, J=3 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.05 (d, J=3 Hz, 1H), 6.90(dd, J=3.0, 8.4 Hz, 1H), 6.86 (s, 2H), 6.40 (d, J=3 Hz, 1H), 3.85 (s,3H), 3.76 (s, 3H), 3.68 (s, 6H).

EXAMPLE 24N-(4-(dimethylamino)phenyl)-3,4,5-trimethoxybenzenesulfonamide

Example 21A (195 mg) was processed as described in Example 21B(substituting N′,N′-dimethyl-1,4-benzenediamine for 4-methoxyaniline) toprovide 200 mg of the desired product.

MS (DCI/NH₃) m/z 367 (M+H)⁺; ¹H NMR (DMSO-d₆, 300 MHz) δ 9.55 (s, 1H),6.93 (s, 2H), 6.90 (d, J=9 Hz, 2H), 6.86 (s, 1H), 6.61 (d, J=9 Hz, 2H),3.75 (s, 3H), 3.74 (s, 6H), 2.81 (s, 6H).

EXAMPLE 25N-(4-fluoro-3-methoxyphenyl)-3,4,5-trimethoxybenzenesulfonamide

Example 21A (250 mg) was processed as described in Example 21B(substituting 3-fluoro-4-methoxyaniline for 4-methoxyaniline) to provide310 mg of the desired product.

MS (DCI/NH₃) m/z 371 (M+H)⁺ and 389 (M+NH₄)⁺; ¹H NMR (DMSO-d₆, 300 MHz)δ 10.05 (s, 1H), 7.08 (d, J=9.3 Hz, 1H), 6.98 (s, 2H), 6.86 (d, J=9.3Hz, 1H), 3.76 (s, 6H), 3.70 (s, 3H), 3.64 (s, 3H).

EXAMPLE 263,4,5-trimethoxy-N-(4-(trifluoromethoxy)phenyl)benzenesulfonamide

Example 21A (125 mg) was processed as described in Example 21B(substituting 4-trifluoromethoxyaniline for 4-methoxyaniline) to provide125 mg of the desired product.

MS (DCI/NH₃) m/z 407 (M+H)⁺ and 425 (M+NH₄)⁺; ¹H NMR (DMSO-d₆, 300 MHz)δ 10.37 (s, 1H), 7.29 (d, J=9.3 Hz, 2H), 7.21 (d, J=9.3 Hz, 2H), 6.99(s, 2H), 3.75 (s, 6H), 3.69 (s, 3H).

EXAMPLE 273,4,5-trimethoxy-N-(2,3,4,5,6-pentafluorophenyl)benzenesulfonamide

Example 21A (125 mg) was processed as described in Example 21B(substituting 2,3,4,5,6-pentafluoroaniline for 4-methoxyaniline) toprovide 120 mg of the desired product.

MS (DCI/H₃) m/z 413 (M+H)⁺ and 431 (M+NH₄)⁺; ¹H NMR (DMSO-d₆, 300 MHz) δ7.02 (s, 2H), 3.81 (s, 3H), 3.79 (s, 6H).

EXAMPLE 28N-(3-amino-4-methoxyphenyl)-3,4,5-trimethoxybenzenesulfonamidehydrochloride Example 28A tert-butyl 2-methoxy-5-nitrophenylcarbamate

A solution of 2-methoxy-5-nitroaniline (2.0 g, 12 mmol) indichloromethane was treated sequentially with NaHCO₃ and di(tert-butyl)dicarbonate, stirred at room temperature overnight, treated with DMAP(10 mgs) and triethylamine (600 μL, 4 mmol), stirred at room temperaturefor 2 days, neutralized with 1M HCl, and extracted with ethyl acetate(500 mL). The organic layer was dried (Na₂SO₄), filtered, andconcentrated. The concentrate was purified by flash chromatography onsilica gel with 5% methanol:dichloromethane to provide 3 g of thedesired product.

EXAMPLE 28B tert-butyl 5-amino-2-methoxyphenylcarbamate

A solution of Example 28A in 1:1 THF:methanol (40 mL) was treated with10% palladium on carbon (800 mg), stirred under hydrogen (1 atm) for onehour, filtered through diatomaceous earth (Celite®), and concentrated toprovide the desired product.

EXAMPLE 28CN-(3-tert-butoxycarbonylamino-4-methoxyphenyl)-3,4,5-trimethoxybenzenesulfonamide

Example 21A (200 mg) was processed as described in Example 21B(substituting Example 28B for 4-methoxyaniline) to provide 300 mg of thedesired product.

EXAMPLE 28DN-(3-amino-4-methoxyphenyl)-3,4,5-trimethoxybenzenesulfonamidehydrochloride

A solution of Example 28C in dichloromethane (1 mL) was treated with4.0M HCl in dioxane, stirred for 1 hour, concentrated to a fraction ofits original volume, and treated with diethyl ether to precipitate 250mg of the desired product.

MS (DCI/NH₃) m/z 369 (M+H)⁺ and 386 (M+NH₄)⁺; ¹H NMR (DMSO-d₆, 300 MHz)δ 10.01 (s, 1H), 7.03 (d, 1H), 7.00 (s, 2H), 6.97 (d, 1H), 6.94 (s, 1H),3.77 (s, 6H), 3.70 (s, 3H).

EXAMPLE 29 3,4,5-trimethoxy-N-(1-methyl-1H-indol-4-yl)benzenesulfonamideEXAMPLE 29A 1-methyl-4-nitro-1H-indole

A solution of 4-nitroindole (500 mg, 3.1 mmol) in THF (15 mL) at 0° C.was treated portionwise with NaH (290 mg, 9.3 mmol), stirred for 30minutes, treated dropwise with methyl iodide (0.95 mL, 15.5 mmol),warmed to room temperature for 18 hours, treated sequentially with waterand ethyl acetate (200 mL), and washed with brine (100 mL). The organiclayer was dried (Na₂SO₄), filtered, and concentrated to provide thedesired product, which was used in the next step without furtherpurification.

EXAMPLE 29B 1-methyl-1H-indol-4-amine

Example 29A (500 mg) was processed as described in Example 28B toprovide 400 mg of the desired product.

EXAMPLE 29C 3,4,5-trimethoxy-N-(1-methyl-1H-indol4-yl)benzenesulfonamide

Example 29B (82 mg, 0.56 mmol) was dissolved in pyridine (1 mL), treatedportionwise with Example 21A, (150 mg, 0.56 mmol) in THF (1 mL), stirredfor 18 hours, concentrated, treated with a small amount of THF todissolve the concentrate, and treated with water with vigorous stirring.The precipitate was filtered and dried in a vacuum oven to provide 180mg of the desired product.

MS (DCI/NH₃) m/z 377 (M+H)⁺ and 394 (M+NH₄)⁺; ¹H NMR (300 MHz, CDCl₃) δ9.93 (s, 1H), 7.20 (d, J=3 Hz, 1H), 7.18 (d, J=6 Hz, 1H), 7.05 (d, J=7.5Hz, 1H), 6.99 (s, 2H), 6.95 (dd, J=0.6, 7.5 Hz, 1H), 3.71 (s, 3H), 3.68(s, 6H), 3.64 (s, 3H).

EXAMPLE 30 3,4,5-trimethoxy-N-(1-methyl-1H-indol-6-yl)benzenesulfonamide

Example 21A (150 mg) was processed as described in Example 21B(substituting 1-methyl-1H-indol-6-amine for 4-methoxyaniline) to provide200 mg of the desired product.

MS (DCI/NH₃) m/z 377 (M+H)⁺ and 394 (M+NH₄)⁺; ¹H NMR (DMSO-d₆, 300 MHz)δ 9.92 (s, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.25 (d, J=3 Hz, 1H), 7.16 (s,1H), 7.00 (s, 2H), 6.78 (dd, J=1.85, 8.4 Hz, 1H), 6.33 (d, 1H), 3.70 (s,6H), 3.68 (s, 3H), 3.66 (s, 3H).

EXAMPLE 31 N-(1H-indol-5-yl)-3,4,5-trimethoxybenzenesulfonamide

Example 21A (100 mg) was processed as described in Example 21B(substituting 1H-indol-5-amine for 4-methoxyaniline) to provide 110 mgof the desired product.

MS (DCI/NH₃) m/z 363 (M+H)⁺ and 380 (M+NH₄)⁺; ¹H NMR (DMSO-d₆, 300 MHz)δ 11.06 (s, 1H), 9.72 (s, 1H), 7.31 (t, J=2.7 Hz, 1H), 7.26 (d, J=1.8Hz, 1H), 7.24 (s, 1H), 6.95 (s, 2H), 6.85 (dd, J=1.8, 8.7 Hz, 1H), 6.35(t, J=2.7 Hz, 1H), 3.69 (s, 6H), 3.66 (s, 3H).

EXAMPLE 32N-(1,2-dimethyl-1H-indol-5-yl)-3,4,5-trimethoxybenzenesulfonamideExample 32A 1,2-dimethyl-1H-indol-5-amine

A solution of 1,2-dimethyl-5-nitro-1H-indole (500 mg) in 1:1THF:methanol (10 mL) was treated with 10% palladium on carbon (100 mg),stirred under hydrogen (1 atm) for 1 hour, filtered through diatomaceousearth (Celite®), and concentrated. The crude product was used withoutfurther purification in the next step.

EXAMPLE 32BN-(1,2-dimethyl-1H-indol-5-yl)-3,4,5-trimethoxybenzenesulfonamide

Example 21A (100 mg) was processed as described in Example 23B(substituting Example 32A for 4-methoxyaniline) to provide 115 mg of thedesired product.

MS (DCI/NH₃) m/z 391 (M+H)⁺ and 408 (M+NH₄)⁺; ¹H NMR (DMSO-d₆, 300 MHz)δ 9.71 (s, 1H), 7.23 (d, J=9 Hz, 1H), 7.15 (d, J=1.8 Hz, 1H), 6.96 (s,2H), 6.82 (dd, J=1.8, 9 Hz, 1H), 6.12 (s, 1H), 3.70 (s, 6H), 3.66 (s,3H), 3.58 (s, 3H), 2.34 (s, 3H).

EXAMPLE 33 N-(3-chloro-1H-indol-5-yl)-3,4,5-trimethoxybenzenesulfonamide

A solution of Example 31 (51 mg, 0.14 mmol) in dichloromethane (1.5 mL)and DMF (50 μL) was treated with N-chlorosuccinimide (21 mg, 0.15 mmol),stirred for 2 hours, and treated sequentially with water (1 mL) andethyl acetate (10 mL). The organic layer was washed sequentially with0.2 MHCl (5 mL) and saturated aqueous NaHCO₃ (5 mL), dried (Na₂SO₄),filtered, and concentrated to provide 25 mg of the desired product.

MS (DCI/NH₃) 414 (M+NH₄)⁺; ¹H NMR (DMSO-d₆, 300 MHz) δ 9.88 (s, 1H),7.49 (d, 1H), 7.32 (s, 1H), 7.29 (s, 1H), 7.18 (d, J=1.8 Hz, 1H), 6.97(s, 2H), 6.94 (d, J=1.8 Hz, 1H), 3.70 (s, 6H), 3.67 (s, 3H).

EXAMPLE 34 N-(1H-indazol-5-yl)-3,4,5-trimethoxybenzenesulfonamide

Example 21A (100 mg) was processed as described in Example 21B(substituting 1H-indazol-5-amine for 4-methoxyaniline) to provide 110 mgof the desired product.

MS (DCI/NH₃) m/z 364 (M+H)⁺ and 381 (M+NH₄)⁺; ¹H NMR (DMSO-d₆, 300 MHz)δ 13.02 (s, 1H), 9.95 (s, 1H), 8.00 (s, 1H), 7.45 (d, J=2.1 Hz, 1H),7.42 (s, 1H), 7.11 (dd, J=2.1, 8.7 Hz, 1H), 6.95 (s, 2H), 3.69 (s, 6H),3.66 (s, 3H).

EXAMPLE 35 3,4,5-trimethoxy-N-(1-methyl-1H-benzimidazol-6-yl)benzenesulfonamide

5-Nitrobenzimidazole (500 mg) was processed as described for4-nitroindole in Examples 29A, 29B, and 29C to provide both methylatedisomers. The isomers were separated by flash column chromatography onsilica gel with 1% methanol:dichloromethane to provide 133 mg of thedesired compound as the less polar isomer.

MS (DCI/NH₃) m/z 378 (M+H)⁺; ¹H NMR (DMSO-d₆, 300 MHz) δ 10.08 (s, 1H),8.10 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.30 (d, J=1.8 Hz, 1H), 7.01 (s,2H), 6.93 (dd, J=1.8, 8.4 Hz, 1H), 3.75 (s, 3H), 3.71 (s, 6H), 3.67 (s,3H).

EXAMPLE 363,4,5-trimethoxy-N-(1-methyl-1H-benzimidazol-5-yl)benzenesulfonamide

5-Nitrobenzimidazole (500 mg) was processed as described in Example 35to provide 167 mg of the desired compound as the more polar isomer.

MS (DCI/NH₃) m/z 378 (M+H)⁺; ¹H NMR (DMSO-d₆, 300 MHz) δ 9.98 (s, 1H),8.13 (s, 1H), 7.44 (d, J=8.7 Hz, 1H), 7.35 (d, J=1.8 Hz, 1H), 7.05 (dd,J=1.8, 8.7 Hz, 1H), 6.99 (s, 2H), 3.77 (s, 3H), 3.71 (s, 6H), 3.66 (s,3H).

EXAMPLE 37 3,4,5-trimethoxy-N-methyl-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide

A solution of Example 23 (50 mg, 0.13 mmol) in THF (1 mL) at 0° C. wastreated with NaH (60% suspension in mineral oil, 15 mg, 0.39 mmol) inportions, stirred at 0° C. for 30 minutes, treated dropwise with methyliodide (42 μL, 0.65 mmol warmed to room temperature overnight. Theproduct was absorbed on silica gel and purified by flash columnchromatography using 1% Methanol:Dichloromethane as the eluent. Thisafforded the product as a solid (35 mg, 68%) plus some unreactedstarting material.

MS (DCI/NH₃) m/z 391 (M+H)⁺ and 408 (M+NH₄)⁺; ¹H NMR (DMSO-d₆, 300 MHz)δ 7.40 (d, J=8.7 Hz, 1H), 7.37 (d, J=3 Hz, 1H), 7.25 (d, J=2.1 Hz, 1H),6.87 (dd, J=2.1, 8.7 Hz, 1H), 6.68 (s, 2H), 6.27 (d, J=8.1 Hz, 1H), 4.03(s, 3H), 3.75 (s, 3H), 3.73 (s, 6H).

EXAMPLE 383,4,5-trimethoxy-N-(2-(dimethylamino)ethyl)-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide

A solution of Example 23 (50 mg, 0.13 mmol) in THF (2 mL) was treatedsequentially with triphenylphosphine (52 mh, 0.19 mmol),N,N-dimethyl-2-aminoethanol (17 μL, 0.16 mmol), anddiethylazodicarboxylate (31 μL, 0.19 mmol), stirred at room temperatureovernight, treated with silica gel, and concentrated. The mixture waspurified by flash column chromatography on silica gel with 1%methanol:dichloromethane to provide 46 mg of the desired product.

MS (DCI/NH₃) m/z 448 (M+H)⁺ and 470 (M+Na)⁺; ¹H NMR (300 MHz, CDCl₃) δ7.40 (d, J=8.7 Hz, 1H), 7.38 (d, J=3 Hz, 1H), 7.26 (d, J=2.1 Hz, 1H),6.83 (dd, J=2.1, 8.7 Hz, 1H), 6.79 (s, 2H), 6.41 (d, J=3 Hz, 1H), 3.78(s, 3H), 3.75 (s, 3H), 3.70 (s, 6H), 3.64 (t, 2H), 2.22 (t, 2H) 2.08 (s,6H).

EXAMPLE 39 1H-indol-5-ol, (3,4,5-trimethoxybenzenesulfonate) ester

A solution of 5-hydroxyindole (CAS number 13523-92-7, 253 mg, 1.9 mmol)in dichloromethane (15 mL) and pyridine (0.5 mL) was treatedsequentially with Example 21A (507 mg, 1.9 mmol) and a catalytic amountof DMAP, stirred for 1 week, and washed with saturated CuSO₄. Theorganic layer was dried (MgSO₄), filtered, and concentrated.Chromatography of the concentrate on silica gel with 30% ethylacetate/hexane provided 520 mg of the desired compound as a whitecrystalline solid.

MS (ESI/NH₃) m/z 364 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 8.24 (br s, 1H),7.29-7.25 (m, 3H), 7.02 (s, 2H), 6.82 (dd, J=2.2, 8.8, 1H), 6.51 (m,1H), 3.92 (s, 3H), 3.78 (s, 6H).

EXAMPLE 40 3,4,5-trimethoxyphenyl) 4-methoxybenzenesulfonate

3,4,5-trimethoxyphenol (504 mg) was processed as described in Example 43(substituting 4-methoxybenzenesulfonyl chloride for 4-methoxymetanilylfluoride) to provide 500 mg of the desired product.

MS (ESI/NH₃) m/z 355 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.81-7.77 (m,2H), 7.01-6.98 (m, 2H), 6.20 (s, 2H), 3.89 (s, 3H), 3.80 (s, 3H), 3.72(s, 6H).

EXAMPLE 41 (3 4,5-trimethoxyphenyl) 4-methylbenzenesulfonate

3,4,5-trimethoxyphenol (497 mg) was processed as described in Example 43(substituting para-toluenesulfonyl chloride for 4-methoxymetanilylfluoride) to provide 770 mg of the desired product.

MS (ESI/NH₃) m/z 339 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.75 (d, J=8.5,2H), 7.34 (d, J=8.1, 2H), 6.19 (s, 2H), 3.80 (s, 3H), 3.70 (s, 6H), 2.46(s, 3H).

EXAMPLE 42 1H-indol-5-yl 3,4,5-trimethoxybenzenesulfonate

Example 21A (726 mg) was processed as described in Example 39(substituting 1-methyl-1H-indol-5-ol for 5-hydroxyindole to provide 650mg of the desired product. MS (ESI/NH₃) m/z 395 (M+NH₄)⁺; ¹H NMR (300MHz, CDCl₃) δ 7.24 (d, J=2.4, 1H), 7.19 (d, J=8.8, 1H), 7.09 (d, J=3.1,1H), 7.02 (s, 2H), 6.85 (dd, J=2.4, 8.8, 1H), 6.43 (dd, J=0.7, 3.1, 1H),3.92 (s, 3H), 3.79 (s, 6H), 3.77 (s, 3H).

EXAMPLE 43 (3,4,5-trimethoxyphenyl) 3-amino-4-methoxybenzenesulfonate

A solution of 3,4,5-trimethoxyphenol (505.7 mg, 2.75 mmol) indichloromethane (28 mL) was treated sequentially with triethylamine (1.2mL), 4-methoxymetanilyl fluoride (572.5 mg, 2.75 mmol), andtert-butylammonium iodide (106 mg, 0.287 mmol), stirred overnight, andwashed once with 1M Na₂CO₃. The organic layer was separated, dried(MgSO₄), filtered, and concentrated. Chromatography of the concentrateon silica gel with 40% ethyl acetate/hexanes provided 356 mg of thedesired compound.

MS (ESI/NH₃) m/z 370 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.25-7.20 (m,2H). 6.84 (d, J=8.5, 1H), 6.23 (s, 2H), 3.93 (s, 3H), 3.75 (s, 3H), 3.73(s, 6H).

EXAMPLE 44 (3,4,5-trimethoxyphenyl)-4-(dimethylamino)benzenesulfonate

4-(Dimethylamino)benzenesulfonyl chloride (prepared as described in J.Am. Chem. Soc. 1997, 99:3, 851-858, 1.93 g) was processed as describedfor 4-methoxymetanilyl fluoride in Example 43 to provide 2.55 g of thedesired product.

MS (ESI/NH₃) m/z 368 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.66 (d, J=8.8,2H), 6.66 (d, J=9.2, 2H), 6.22 (s, 2H), 3.79 (s, 3H), 3.71 (s, 6H), 3.07(s, 6H).

EXAMPLE 45 4-methylphenyl 3,4,5-trimethoxybenzenesulfonate

Example 21A (103 mg) was processed as described in Example 39(substituting 4-methylphenol for 5-hydroxyindole to provide 26.6 mg ofthe desired product.

MS (ESI/NH₃) m/z 356 (M+NH₄)⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.11-7.08 (m,2H), 7.01 (s, 2H), 6.90-6.87 (m, 2H), 3.92 (s, 3H), 3.83 (s, 6H), 2.32(s, 3H).

EXAMPLE 46 3,4,5-trimethoxyphenyl 1-methyl-5-indolinesulfonate EXAMPLE46A 1-methyl-5-indolinesulfonyl chloride

A solution of chlorosulfonic acid at 0° C. (5 mL, 75 mmol) was treatedportionwise with 1-methylindoline (CAS No. [824-21-5], 1.96 g, 14.7mmol), warmed to room temperature, heated at 75° C. for 40 minutes,cooled, and poured onto ice to provide a solid. The solid was collectedby suction filtration, washed with water, and dried to provide 927 mg ofthe desired product.

¹H NMR (300 MHz, CDCl₃) 7.33 (dd, J=1.8, 7.7, 1H), 7.19 (d, J=7.7, 1H),6.93 (d, J=1.8, 1H), 3.51 (t, J=8.5, 2H), 3.07 (t, J=8.5, 2H), 2.86 (s,3H).

EXAMPLE 46B 3,4,5-trimethoxyphenyl 1-methyl-5-indolinesulfonate

3,4,5-trimethoxyphenol (103 mg) was processed as described in Example 43(substituting Example 52A for 4-methoxymetanilyl fluoride) to provide 22mg of the desired product.

MS (ESI/NH₃) m/z 380 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.12 (s, 2H),6.79 (s, 1H), 6.24 (s, 2H), 3.80 (s, 3H), 3.72 (s, 6H), 3.46 (t, 2H),3.02 (t, 2H), 2.77 (s, 3H).

EXAMPLE 47 4-methoxyphenyl 3,4,5-trimethoxybenzenesulfonate

Example 21A (104 mg) was processed as described in Example 39(substituting 4-methoxyphenol for 5-hydroxyindole to provide 69.6 mg ofthe desired product. MS (ESI/NH₃) m/z 372 (M+NH₄)⁺; ¹H NMR (300 MHz,CDCl₃) δ 7.00 (s, 2H), 6.93-6.89 (m, 2H), 6.82-6.78 (m, 2H), 3.92 (s,3H), 3.83 (s, 6H), 3.68 (s, 3H).

EXAMPLE 48 tert-butyl2-((1-methyl-1H-indol-5-yl)((3,4,5-trimethoxyphenyl)sulfonyl)amino)ethylcarbamate

Example 23 (50 mg) was processed as described in Example 38(substituting N-(tert-butoxycarbonyl)ethanolamine forN,N-dimethyl-2-aminoethanol) to provide 60 mg of the desired product.

MS (DCI/NH₃) m/z 520 (M+H)⁺ and 537 (M+NH₄)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ 7.40 (d, 1H), 7.38 (d, J=3 Hz, 1H), 7.28 (d, 1H), 6.83 (m, 1H), 6.76(s, 2H), 6.40 (d, J=3 Hz, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 3.71 (s, 6H),3.57 (s, 2H), 3.16 (d, 1H), 2.96 (q, 2H), 1.32 (s, 9H).

EXAMPLE 49N-(2-hydroxyethyl)-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide

Example 23 (50 mg) was processed as described in Example 38(substituting ethylene glycol for N,N-dimethyl-2-aminoethanol) toprovide 60 mg of the desired product.

MS (DCI/NH₃) m/z 420 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.97 (s, 1H),7.28 (d, J=2.7 Hz, 1H), 7.26 (d, J=2.1 Hz, 1H), 6.96 (s, 2H), 6.90 (dd,J=8.4 Hz, 2.1 Hz, 1H), 6.34 (d, J=2.7 Hz, 1H), 4.03 (q, J=6.9 Hz, 2H),3.72 (s, 3H), 3.69 (s, 3H), 3.66 (s, 6H), 1.17 (t, J=6.9 Hz, 2H).

EXAMPLE 50N-(2,3-dihydro-1,4-benzodioxin-6-yl)-3,4,5-trimethoxybenzenesulfonamide

Example 21A (500 mg) was processed as described in Example 21B(substituting 1,4-benzodioxane-6-amine for 4-methoxyaniline) to provide651 mg of the desired product.

MS (DCI/NH₃) m/z 381 (M+H)⁺ and 399 (M+NH₄)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ 9.85 (s, 1H), 6.97 (s, 2H), 6.73 (d, 1H), 6.57 (m, 2H), 4.16 (s, 2H),3.76 (s, 6H), 3.70 (s, 3H).

EXAMPLE 51N-(2-aminoethyl)-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamidehydrochloride EXAMPLE 51A benzyl2-((1-methyl-1H-indol-5-yl)((3,4,5-trimethoxyphenyl)sulfonyl)amino)ethylcarbamate

Example 23 (50 mg) was processed as described in Example 38(substituting benzyl N-(2-hydroxyethyl) carbamate forN,N-dimethyl-2-aminoethanol) to provide 46 mg of the desired product.

EXAMPLE 51BN-(2-aminoethyl)-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide

A solution of Example 51A in methanol:THF (1 mL:1 mL) was treated with10% palladium on carbon (30 mg), stirred under with hydrogen (1 atm) for2 hours, filtered through diatomaceous earth (Celite®), and concentratedto provide the desired compound.

EXAMPLE 51CN-(2-aminoethyl)-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamidehydrochloride

Example 51B, in less than 1 mL of methanol, was treated with severaldrops of 1M HCl in diethyl ether to provide a cloudy, acidic solution.Diethyl ether was added to cause precipitation. The precipitate wasfiltered and oven dried to provide 20 mg of the desired product.

MS (DCI/NH₃) m/z 420 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 7.41 (d, J=8.7Hz, 1H), 7.38 (d, J=3 Hz, 1H), 7.28 (d, J=2.1 Hz, 1H), 6.83 (dd, J=8.7Hz, 2.1 Hz, 1H), 6.77 (s, 2H), 6.41 (d, J=3 Hz, 1H), 3.79 (s, 3H), 3.76(s, 3H), 3.70 (s, 6H).

EXAMPLE 523-amino-4-methoxy-N-methyl-N-(3,4,5-trimethoxyphenyl)benzenesulfonamideExample 52A4-methoxy-N-methyl-3-nitro-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide

A solution of Example 9B (100 mg, 0.25 mmol) in THF (2 mL) at ° C. wastreated with sodium hydride (29 mg, 60% dispersion in mineral oil, 0.75mmol), stirred for 20 minutes, treated dropwise with methyl iodide (94μL, 1.5 mmol), warmed to room temperature, stirred for 18 hours, treatedwith water, and extracted with ethyl acetate. The extract wasconcentrated, and the concentrate was used in the next step withoutfurther purification.

EXAMPLE 52B3-amino-4-methoxy-N-methyl-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide

A solution of Example 52A (00 mg) in methanol:THF (1 mL:1 mL) wastreated with 10% palladium on carbon, stirred under hydrogen (1atm) for4 hours, filtered through diatomaceous earth (Celite®), andconcentrated. The concentrate was purified by flash columnchromatography on silica gel with 2% methanol/dichloromethane to provide31 mg of the desired product.

EXAMPLE 52C3-amino-4-methoxy-N-methyl-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide

A solution of Example 52B in less than 1 mL of methanol was treated withseveral drops of 1M HCl in diethyl ether to provide a cloudy, acidicsolution and treated with diethyl ether to precipitate the product. Theprecipitate was filtered and oven dried to provide 13.5 mg of thedesired product.

MS (DCI/NH₃) m/z 383 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 6.83 (d, J=2.1Hz, 1H), 6.75 (d, J=8.1 Hz, 1H), 6.66 (dd, J=8.1 Hz, 2.1 Hz, 1H), 6.31(s, 2H), 3.66 (s, 6H), 3.64 (s, 3H), 3.02 (s, 3H).

EXAMPLE 53 1-ethyl-N-(3 4 5-trimethoxyphenyl)-1H-indole-5-sulfonamide

Example 18 (50 mg) was processed as described in Example 19(substituting ethyl iodide for methyl iodide) to provide 40 mg of thedesired product.

MS (DCI/NH₃) m/z 391 (M+H)⁺ and 408 (M+NH₄)⁺; ¹H NMR (300 MHz, DMSO-d₆)δ 9.93 (s, 1H), 8.06 (d, J=2.1 Hz, 1H), 7.70 (d, J=3 Hz, 1H), 7.63 (m,1H), 7.60 (d, J=2.1 Hz, 1H), 6.62 (d, J=3 Hz, 1H), 6.39 (s, 2H), 4.23(q, J=7.5 Hz, 2H), 3.61 (s, 6H), 3.52 (s, 3H), 1.34 (t, J=7.5 Hz, 3H).

EXAMPLE 54N-acetyl-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide

A solution of Example 23 (50 mg, 0.13 mmol) in THF (1 mL) at −25° C. wastreated with sequentially with triethylamine (24 μL, 0.17 mmol), lithiumchloride (6 mg, 0.14 mmol), and acetic anhydride (25 μL, 0.26mmol)dropwise, warmed to room temperature, stirred for 18 hours, andconcentrated. The concentrate was treated with ethyl acetate and washedwith water and brine. The organic layer was dried (Na₂SO₄), filtered andconcentrated. The concentrate was purified by flash columnchromatography on silica gel with 1% methanol:dichloromethane to provide35 mg of the desired product.

MS (DCI/NH₃) m/z 419 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 7.59 (d, J=2.1Hz, 1H), 7.57 (d, J=8.7 Hz, 1H), 7.47 (d, J=3.3 Hz, 1H), 7.17 (s, 2H),7.13 (dd, J=8.7, 2.1 Hz, 1H), 6.53 (dd, J=2.1, 3.3 Hz, 1H), 3.86 (s,6H), 3.85 (s, 3H), 3.73 (s, 3H), 1.81 (s, 3H).

EXAMPLE 55 3,4,5-trimethoxy-N-(6-quinolinyl)benzenesulfonamide

Example 21A (185 mg) was processed as described in Example 21B(substituting 6-aminoquinoline for 4-methoxyaniline) to provide 180 mgof the desired product.

MS (DCI/NH₃) m/z 375 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 10.58 (s, 1H),8.77 (dd, J=1.5 Hz, 4.0 Hz, 1H), 8.31 (d, J=8.7 Hz 1H), 7.91 (d, J=9 Hz,1H), 7.68 (d, J=2.4, 1H), 7.53 (dd, J=9 Hz, 2.4 Hz, 1H), 7.46 (dd, J=8.7Hz, 4.2 Hz, 1H), 3.73 (s, 6H), 3.65 (s, 3H).

EXAMPLE 56N-(2-hydroxyethyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide

Example 19 (50 mg) was processed as described in Example 38(substituting ethylene glycol for N,N-dimethyl-2-aminoethanol) toprovide 25.5 mg of the desired product.

MS (DCI/NH₃) m/z 421 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 7.86 (d, J=1.8Hz, 1H), 7.64 (d, J=8.7 Hz, 1H), 7.54 (d, J=3.3 Hz, 1H), 7.32 (dd, J=8.7Hz, 1.8 Hz, 1H), 6.65 (d, J=3.3 Hz, 1H), 6.29 (s, 2H), 4.03 (q, J=6.9Hz, 2H), 3.84 (s, 3H), 3.64 (s, 3H), 3.58 (s, 6H), 2.52 (d, J=6.9 Hz,2H).

EXAMPLE 57N-(2-fluoroethyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide

Example 19 (50 mg) was processed as described in Example 38(substituting 2-fluoroethanol for N,N-dimethyl-2-aminoethanol) toprovide 30 mg of the desired product.

MS (DCI/NH₃) m/z 423 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 7.90 (d, J=1.8Hz, 1H), 7.64 (d, J=8.7 Hz, 1H), 7.54 (d, J=3.3 Hz, 1H), 7.40 (dd, J=8.7Hz, 1.8 Hz, 1H), 6.63 (d, J=3.3 Hz, 1H), 6.23 (s, 2H), 4.48 (t, 2H),4.32 (t, 2H), 3.86 (s, 3H), 3.65 (s, 3H), 3.54 (s, 6H).

EXAMPLE 58N-ethyl-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide

Example 19 (50 mg) was processed as described in Example 38(substituting ethanol for N,N-dimethyl-2-aminoethanol) to provide 35 mgof the desired product.

MS (DCI/NH₃) m/z 405 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 7.89 (d, J=1.8Hz, 1H), 7.64 (d, J=8.7 Hz, 1H), 7.54 (d, J=3.3 Hz, 1H), 7.40 (dd, J=8.7Hz, 1.8 Hz, 1H), 6.64 (d, J=3.3 Hz, 1H), 6.22 (s, 2H), 3.86 (s, 3H),3.65 (s, 3H), 3.56 (s, 6H), 3.49 (q, 2H), 0.97 (t, 3H).

EXAMPLE 59 4-nitrophenyl-3,4,5-trimethoxybenzenesulfonate

A solution of 21A (2.02 g, 7.57 mmol) in dichloromethane (31 mL) wastreated with 4-nitrophenol (1.06 g, 7.62 mmol), pyridine, and DMAP,stirred overnight at room temperature, diluted with ethyl acetate andwashed with 1M Na₂CO₃. The organic layer was dried (MgSO₄), filtered,and concentrated to provide 1.76 g of the title compound.

MS (APCI) m/z 368 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) 8.23 (m, 2H), 7.23 (m,2H), 7.05 (s, 2H), 3.94 (s, 3H), 3.86 (s, 6H).

EXAMPLE 60 4-aminophenyl-3,4,5-trimethoxybenzenesulfonate

A slurry of Example 59 (917 mg, 2.48 mmol) and Pd/C in ethyl acetate wasstirred under hydrogen for 18 hours, filtered and concentrated toprovide 741 mg of the desired product.

MS (ESI) m/z 357 (M+NH₄)⁺; ¹H NMR (300 MHz, CDCl₃) 7.01 (s, 2H), 6.80(d, J=8.1, 2H), 6.61 (d, J=8.5, 2H), 3.93 (s, 3H), 3.85 (s, 6H).

EXAMPLE 61 4-dimethylaminophenyl-3,4,5-trimethoxybenzenesulfonate

A stirred solution of Example 60 (142 mg, 0.418 mmol) in acetic acid(4.5 mL) was treated with paraformaldehyde (126 mg, 419 mmol) andNaCNBH₃ (131 mg, 2.09 mmol), stirred overnight at room temperature, andconcentrated. The concentrate was dissolved in ethyl acetate, washedwith saturated sodium bicarbonate, dried (MgSO₄), filtered, andconcentrated to provide 76 mg of the desired product.

MS (ESI) m/z 368 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) 7.01 (s, 2H), 6.84 (d,J=8.8, 2H), 6.57 (d, J=8.8, 2H), 3.92 (s, 3H), 3.83 (s, 6H).

EXAMPLE 62 3,4,5-trimethoxyphenyl 6-methoxy-3-pyridinesulfonate EXAMPLE62A 2-methoxy-5-pyridinesulfonylchloride

The procedure in J. Het. Chem. 23, 1253 (1986) was slightly modified tomake the title compound. A stirred solution of 2-methoxy-5-aminopyridine(1.06 g, 8.61 mmol) in acetic acid (8.2 mL) and 12M HCl (15 mL) at −10°C. was slowly treated with a solution of NaNO₂ (633 mg, 9.17 mmol) inwater (2.2 mL), stirred at −5° C. for 30 minutes, treated sequentiallywith a solution of CuCl₂ (463 mg, 3.44 mmol), SO₂ (4 mL) in acetic acid(11 mL), and water (2 mL), stirred for 2 hours at −5° C. and at roomtemperature for 18 hours, poured over ice, filtered, and concentrated toprovide 725 mg of the desired product. ¹H NMR (300 MHz, CDCl₃) 8.84 (d,J=2.7, 1H), 8.11 (dd, J=2.7, 8.8, 1H), 6.91 (d, J=9.2, 1H), 4.07 (s,3H).

EXAMPLE 62B 3,4,5-trimethoxyphenyl 6-methoxy-3-pyridinesulfonate

A solution of 2-methoxypyridine-5-sulfonylchloride (314 mg, 1.51 mmol)in dichloromethane (15 mL) was treated with triethylamine (0.63 mL) and3,4,5-trimethoxyphenol (279 mg, 1.51 mmol), stirred for 18 hours at roomtemperature, diluted with ethyl acetate, washed three times with 1MNa₂CO₃, dried (MgSO₄), filtered, and concentrated to provide 447 mg ofthe desired product.

MS (ESI) m/z 356 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) 8.61 (d, J=2.7, 1H),7.96 (dd, J=2.4, 11.2, 1H), 6.85 (dd, J=0.7, 9.5, 1H), 6.26 (s, 2H),4.02 (s, 3H), 3.80 (s, 3H), 3.75 (s, 6H).

EXAMPLE 63 1-methyl-2-oxo-1,2-dihydro-4-pyridinyl3,4,5-trimethoxybenzenesulfonate

A solution of 4-hydroxy-1-methyl-1H-pyridin-2-one ([40357-87-7], 44.9mg, 0.358 mmol) in dioxane (2 mL) and DMF (1 mL) was treated withtriethylamine (0.15 mL) and 3,4,5-trimethoxybenzenesulfonylchloride(97.1 mg, 0.358 mmol), stirred for 48 hours at room temperature, dilutedwith ethyl acetate, washed with 1.1M NaHSO₄, dried (MgSO₄), filtered andconcentrated. Chromatography of the concentrate on silica gel with 40%ethyl acetate/hexane provided 47 mg of the desired compound.

MS (ESD m/z 356 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) 7.29 (d, J=7.5, 1H),7.11 (s, 2H), 6.21 (d, J=2.4, 1H), 6.13 (dd, J=2.7, 7.5, 1H), 3.94 (s,3H), 3.92 (s, 6H), 3.51 (s, 3H).

EXAMPLE 64 3,4,5-trimethoxyphenyl3-((3-aminopropanoyl)amino)-4-methoxybenzenesulfonate

A solution of Example 43 (0.148 g, 0.400 mmol) and N-tert-Boc-β-alanine(0.228 g, 1.20 mmol) in DMF (4 mL) was treated with HOOBT (0.260 g, 1.60mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (0.306 g,1.60 mmol), and triethylamine (0.162 g, 1.60 mmol), heated at 50° C. for30 hours, cooled, diluted with ethyl acetate (40 mL), washedsequentially with 2:1:1 water/saturated aqueous sodium bicarbonate/brine(20 mL followed by 2×10 mL) and brine (10 mL), filtered through silicagel with ethyl acetate rinses, and concentrated. The concentrate waspurified by radial chromatography with 1:1 hexane/ethyl acetate toprovide 0.138 g of the N-Boc amide. The amide was stirred in 4M HCl indioxane (2 mL) for two hours and concentrated. The concentrate wasdissolved in a minimal amount of water and lyophilized to provide 0.123g of the desired product.

LRMS (ESI(+)) m/z 441 (M+H)⁺; (ESI(−)) m/z 439 (M−H)⁻; ¹H NMR (DMSO-d₆)δ 2.82 (t, J=6.4 Hz, 3H), 3.06 (t, J=6.4 Hz, 3H), 3.61 (s, 3H), 3.63 (s,6H), 3.96 (s, 3H), 6.30 (s, 2H), 7.29 (d, J=8.8 Hz, 1H), 7.60 (dd,J=2.2, 8.8 Hz, 1H), 7.75-7.81 (br, 3H), 8.62 (d, J=2.2 Hz, 1H),9.85-9.89 (br, 1H).

EXAMPLE 65 3,4,5-trimethoxyphenyl3-(((2R)-2-aminopropanoyl)amino)-4-methoxybenzenesulfonate

Example 43 was processed as described in Example 64 but substitutingN-t-Boc-alanine for N-tert-Boc-β-alanine to provide the desired product.

LRMS (ESI(+)) m/z 441 (M+H)⁺; (ESI(−)) n/z 439 (M−H)⁻; ¹H NMR (DMSO-d₆)δ 1.44 (d, J=6.7 Hz, 3H), 3.61 (s, 3H), 3.63 (s, 6H), 3.98 (s, 3H),4.19-4.28 (br, 1H), 6.31 (s, 2H), 7.43 (d, J=8.9 Hz, 1H), 7.67 (dd,J=2.4, 8.9 Hz, 1H), 8.25-8.32 (br, 3H), 8.49 (d, J=2.4 Hz, 1H), 10.17(s, 1H).

EXAMPLE 66 3,4,5-trimethoxyphenyl3-(((2R)-2-amino-3-methylbutanoyl)amino)-4-methoxybenzenesulfonate

Example 43 was processed as described in Example 64 but substitutingN-t-Boc-valine for N-tert-Boc-β-alanine to provide the desired product.

LRMS (ESI(+)) m/z 469 (M+H)⁺; (ESI(−)) m/z 467 (M−H)⁻; ¹H NMR (DMSO-d₆)δ 0.98 (d, J=7.0 Hz, 6H), 2.09-2.21 (m, 1H), 3.61 (s, 3H), 3.63 (s, 6H),3.98 (s, 3H), 4.04 (d, J=5.2 Hz, 1H), 6.30 (s, 2H), 7.35 (d, J=9.0 Hz,1H), 7.69 (dd, J=2.2, 9.0 Hz, 1H), 8.18-8.34 (Br, 3H), 8.46 (d, J=2.2Hz, 1H), 10.17-10.21 (Br, 1H).

EXAMPLE 67N-((dimethylamino)acetyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide

A solution of Example 19 (1.00 g, 2.66 mmol) in dichloromethane (25 mL)at room temperature was treated with DCC (2.75 g, 13.3 mmol),4-pyrrolidinylpyridine (0.20 g, 1.32 mmol) and N,N-dimethylglycine (0.68g, 6.40 mmol), stirred for 16 hours, diluted with dichloromethane, andfiltered. The filtrate was washed with water, dried (MgSO₄), filtered,and concentrated. The concentrate was treated with dichloromethane,filtered, and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 1.5% methanol/dichloromethane,dissolved in dichloromethane (5 mL) and diethyl ether (5 mL), treatedwith 4M HCl in dioxane (0.55 mL), stirred for 10 minutes, treated withether, and filtered to provide the desired product.

mp: 200-203° C.; MS (ESI(+)) m/z 462 (M+H)⁺; ¹H NMR (DMSO-d₆): δ 8.36(d, J=1.8 Hz, 1H), 7.78 (dd, J₁=8.7 Hz, J₂=1,8 Hz, 1H), 7.73 (d, J=8.7Hz, 1H), 7.61 (d, J=3.0 Hz, 1H), 6.76 (d, J=3.0 Hz, 1H), 6.73 (s, 2H),3.92 (s, 2H), 3.82 (s, 3H), 3.82 (s, 6H), 3.75 (s, 3H), 2.67 (s, 6H);Anal. calcd. for C₂₂H₂₇N₃O₆S.HCl.1.5H₂O: C, 50.43; H, 5.77; N, 8.02.Found: C, 50.50; H, 5.93; N, 8.01.

EXAMPLE 681-methyl-N-(((2S)-1-methylpyrrolidinyl)carbonyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide

The desired product was prepared by substituting N-methyl-L-proline forN,N-dimethylglycine in Example 67.

MS (APCI(+)) m/z 488 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 8.36 (d, J=2 Hz, 1H),7.75 (m, 2H), 7.61 (d, J=3 Hz, 1H), 6.82 (s, 2H), 4.76 (d, J=3 Hz, 1H),4.06 (m, 1H), 3.90 (s, 3H), 3.81 (s, 6H), 3.77 (s, 3H), 3.00 (m, 2H),2.69 (s, 3H), 1.90 (m, 3H), 1.73 (m, 1H).

EXAMPLE 69N-((2S)-2-(dimethylamino)-3-methylbutanoyl)-1-methyl-N-(3.4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide

The desired product was prepared by substituting N,N-dimethyl-L-valinefor N,N-dimethylglycine in Example 67.

MS (ESI(+)) m/z 504 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 8.38 (s, 1H), 7.75 (m,2H), 7.60 (d, J=3 Hz, 1H), 6.76 (d, J=3 Hz, 1H), 6.55 (br s, 2H), 3.89(s, 3H), 3.82 (m, 1H), 3.79 (s, 9H), 2.68 (m, 3H), 2.55 (br s, 3H), 2.26(br s, 1H), 0.91 (m, 3H), 0.75 (m, 3H).

EXAMPLE 70N-((2S)-2-amino-3-methylbutanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide

A solution of Example 19 (400 mg, 1.06 mmol) in dichloromethane (8 mL)at room temperature was treated with DCC (482 mg, 2.42 mmol),4-pyrrolidinopyridine (16 mg, 0.11 mmol), andN-(tert-butoxycarbonyl)-L-valine (462 mg, 2.13 mmol), stirred for 16hours, treated with additional DCC (50 mg, 0.25 mmol) andN-(tert-butoxycarbonyl)-L-valine (50 mg, 0.23 mmol), stirred for 4hours, and filtered. The filtrate was treated with dichloromethane (50mL), washed with water, dried (Na₂SO₄), filtered, and concentrated. Theconcentrate was purified by flash column chromatography on silica gelwith 2% methanol/dichloromethane, dissolved in dioxane (5 mL), treatedwith 4M HCl in dioxane, stirred for 2 hours, treated with ether (75 mL),filtered, and dried to provide the desired product.

MS (ESI(+)) m/z 576 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 8.33 (m, 1H), 7.73 (m,2H), 7.60 (d, J=3 Hz, 1H), 6.75 (d, J=3 Hz, 1H), 6.65 (br s, 2H), 3.80(br s, 7H), 3.76 (s, 3H), 3.57 (s, 3H), 2.10 (m, 1H), 0.80 (d, J=2.4 Hz,3H), 0.78 (d, J=2.7 Hz, 3H).

EXAMPLE 711-methyl-N-((2S)-2-(methylamino)propanoyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide

The desired product was prepared by substitutingN-(tert-butoxycarbonyl)-L-N-methylalanine forN-(tert-butoxycarbonyl)-L-valine in Example 70.

MS (DCI/NH₃) m/z 462 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 8.95 (br s, 2H), 8.33(m, 1H), 7.68-7.78 (m, 2H), 7.60 (d, J=4 Hz, 1H), 6.72 (d, J=4 Hz, 1H),6.70 (br s, 2H), 3.89 (s, 3H), 3.81 (s, 6H), 3.77 (s, 3H), 3.62-3.71 (m,1H), 2.37 (s, 3H), 1.38 (d, J=8 Hz, 3H).

EXAMPLE 72N-((2R)-2-amino-2-phenylethanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide

The desired product was prepared by substituting(S)-N-(tert-butoxycarbonyl)-2-phenylglycine forN-(tert-butoxycarbonyl)-L-valine in Example 70.

MS (ESI(+)) m/z 510 (M+H)⁺; 532 (M+Na)⁺; ¹H NMR (DMSO-d₆) δ 8.52 (br s,3H), 8.34 (m, 1H), 7.74 (s, 1H), 7.63(d, J=3.4 Hz, 1H), 7.41-7.27 (m,3H), 6.83-6.67 (m, 4H), 5.51 (br s, 1H), 4.92 (s, 1H), 3.91 (s, 3H),3.87-3.85 (m, 3H), 3.73 (s, 3H), 3.57 (s, 3H).

EXAMPLE 73N-((2S)-2-amino-3-phenylpropanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide

The desired product was prepared by substitutingN-(tert-butoxycarbonyl)-L-phenylalanine forN-(tert-butoxycarbonyl)-L-valine in Example 70.

MS (ESI(+)) m/z 524 (M+H)⁺; 546 (M+Na)⁺; ¹H NMR (DMSO-d₆) δ 8.44 (br s,3H), 8.32 (m, 1H), 7.74 (d, J=1.6 Hz, 1H), 7.63 (d, J=3.4 Hz, 1H),7.28-7.11 (m, 3H), 6.82-6.77 (m, 4H), 6.00 (br s, 11), 3.91 (s, 3H),3.72-3.67 (m, 9H).

EXAMPLE 741-methyl-N-((2S)-pyrrolidinylcarbonyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide

The desired product was prepared by substitutingN-(tert-butoxycarbonyl)-L-proline for N-(tert-butoxycarbonyl)-L-valinein Example 70.

MS (ESI(+)) m/z 474 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 8.35 (m, 1H), 7.76 (m,2H), 7.61 (d, J=3 Hz, 1H), 6.75 (d, J=3 Hz, 1H), 6.70 (br s, 2H), 4.03(m, 1H), 3.89 (s, 3H), 3.81 (br s, 6H), 3.76 (s, 3H), 3.20 (m, 2H),1.95-1.75 (m, 4H).

EXAMPLE 75N-((2S)-2,6-diaminohexanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide

The desired product was prepared by substitutingN,N-di-(tert-butoxycarbonyl)-L-lysine forN-(tert-butoxycarbonyl)-L-valine in Example 70.

MS (ESI(+)) m/z 505 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 8.30 (m, 1H), 7.73 (m,2H), 7.60 (d, J=3 Hz, 1H), 6.75 (d, J=3 Hz, 1H), 6.65 (br s, 2H), 3.89(s, 3H), 3.80 (m, 6H), 3.76 (s, 3H), 3.59 (m, 1H), 2.67 (m, 2H),1.75-1.20 (m, 6H).

EXAMPLE 76N-((2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide

The desired product was prepared by substitutingN-(tert-butoxycarbonyl)-L-histidine for N-(tert-butoxycarbonyl)-L-valinein Example 70.

mp: 175-177° C.; MS (ESI(+)) m/z 514 (M+H)⁺; ¹H NMR (DMSO-d₆) δ9.03 (s,1H), 8.29 (s, 1H), 7.71 (m, 2H), 7.61 (d, J=3 Hz, 1H), 7.28 (s, 1H),6.75 (d, J=3 Hz, 1H), 6.70 (br s, 2H), 4.01 (m, 1H), 3.89 (s, 3H), 3.79(br s, 6H), 3.76 (s, 3H), 1.72 (m, 2H).

EXAMPLE 77(2S)-2-amino-4-oxo-4-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)butanoicacid

The desired product was prepared by substitutingN-(tert-butoxycarbonyl)-L-aspartic acid 1-tert-butyl ester forN-(tert-butoxycarbonyl)-L-valine in Example 70.

mp: 156-159° C.; MS (ESI(+)) m/z 492 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 8.35 (d,J=2 Hz), 7.75 (m, 2H), 7.60 (d, J=1H), 6.73 (d, J=3 Hz, 1H), 6.63 (br s,2H), 4.01 (m, 1H), 3.88 (s, 3H), 3.82 (s, 6H), 3.76 (s, 3H), 2.80-2.70(m, 2H).

EXAMPLE 78(3S)-3-amino-4-oxo-4-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)butanoicacid

The desired product was prepared by substitutingN-(tert-butoxycarbonyl)-L-aspartic acid 4-tert-butyl ester forN-(tert-butoxycarbonyl)-L-valine in Example 70.

MS (ESI(+)) m/z 492 (M+H)⁺; ¹H NMR (DMSO-d₆): δ 8.33 (m, 1H), 7.73 (m,2H), 7.61 (d, J=3 Hz, 1H), 6.62 (d, J=3 Hz, 1H), 6.40 (s, 2H), 3.95 (m,1H), 3.88 (s, 3H), 3.76 (s, 6H), 3.74 (s, 3H), 2.75 (m, 2H).

EXAMPLE 79(2R)-2-amino-5-oxo-5-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)pentanoicacid

The desired product was prepared by substitutingN-(tert-butoxycarbonyl)-L-glumatic acid 1-tert-butyl ester forN-(tert-butoxycarbonyl)-L-valine in Example 70.

MS (ESI(+)) m/z 506 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 8.31 (br s, 1H), 7.75(dd, J₁=9 Hz, J₂=2 Hz, 1H), 7.69 (d, J=9 Hz, 1H), 7.58 (d, J=3 Hz, 1H),6.72 (d, J=3 Hz, 1H), 6.69 (s, 1H), 6.66 (s, 1H), 4.06 (m, 1H), 3.88 (s,3H), 3.80 (s, 6H), 3.72 (s, 3H), 2.30 (m, 1H), 2.22 (m, 1H), 1.95 (m,1H), 1.80 (m, 1H).

EXAMPLE 80(4S)-4-amino-5-oxo-5-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)pentanoicacid

The desired product was prepared by substitutingN-(tert-butoxycarbonyl)-L-glumatic acid 5-tert-butyl ester forN-(tert-butoxycarbonyl)-L-valine in Example 70.

MS (ESI(+)) m/z 506 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 8.33 (m, 1H), 7.74 (m,2H), 7.60 (d, J=3 Hz, 1H), 6.75 (d, J=3 Hz, 1H), 6.71 (br s, 2H), 4.06(m, 1H), 3.89 (s, 3H), 3.80 (s, 6H), 3.75 (s, 3H), 3.72 (s, 3H), 2.19(m, 2H), 1.95-1.70 (m, 2H).

EXAMPLE 81N-((bis(2-methoxyethyl)amino)acetyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamideEXAMPLE 81A benzyl (bis(2-methoxyethyl)amino)acetate

A solution of benzyl bromoacetate (28.9 g; 96.7 mmol) in dichloromethane(100 mL) at room temperature was treated with2-methoxy-N-(2-methoxyethyl)ethanamine (40.6 g; 305 mmol), stirred for30 minutes, diluted with dichloromethane, washed sequentially withsaturated NH₄Cl, water, and brine, dried (Na₂SO₄), filtered, andconcentrated. The concentrate was purified by flash columnchromatography on silica gel with 40% diethyl ether/dichloromethane toprovide the desired product.

EXAMPLE 81B (bis(2-methoxyethyl)amino)acetic acid

A solution of Example 81A (19.4 g; 69 mmol) and 10% Pd/C (3.5 g) inmethanol (150 mL) at room temperature was stirred under 4 atm of H₂ for17 hours, filtered through diatomaceous earth (Celite®), andconcentrated to provide the desired product.

EXAMPLE 81CN-((bis(2-methoxyethyl)amino)acetyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide

The desired product was prepared by substituting Example 81B forN,N-dimethylglycine in Example 67.

MS (DCI/NH₃) m/z 550 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 8.29 (d, J=2 Hz, 1H),7.77-7.68 (m, 2H), 7.57 (d, J=4 Hz, 1H), 6.73 (d, J=4 Hz, 1H), 6.61 (s,2H), 3.88 (s, 3H), 3.78 (s, 6H), 3.72 (s, 3H), 3.19 (s, 2H), 3.16 (t,J=6 Hz, 4H), 3.04 (s, 6H), 2.61 (t, J=6 Hz, 4H); Anal. calcd. forC₂₆H₃₆ClN₃O₈S: C, 53.28; H, 6.19; N, 7.17; Cl, 6.05. Found: C, 53.28; H,6.03; N, 7.10; Cl, 5.97.

EXAMPLE 821-methyl-N-(4-morpholinylacetyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide

The desired product was prepared by substituting morpholine for2-methoxy-N-(2-methoxyethyl)ethanamine in Example 81.

MS (DCI/NH₃) m/z 504 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 8.29-7.77 (d, J=2 Hz,1H), 7.68 (m, 2H), 7.57 (d, J=4 Hz, 1H), 6.73 (d, J=4 Hz, 1H), 6.63 (s,2H), 3.88 (s, 3H), 3.80 (s, 6H), 3.72 (s, 3H), 3.47-3.41 (m, 4H), 2.94(s, 2H), 2.31-2.27 (m, 4H).

EXAMPLE 831-methyl-N-((4-methyl-1-piperazinyl)acetyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide

The desired product was prepared by substituting N-methylpiperazine for2-methoxy-N-(2-methoxyethyl)ethanamine in Example 81.

MS (DCI/NH₃) m/z 517 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 8.29 (d, J=2 Hz, 1H),7.77-7.68 (m, 2H), 7.57 (d, J=4 Hz, 1H), 6.73 (d, J=4 Hz, 1H), 6.61 (s,2H), 3.88 (s, 3H), 3.78 (s, 6H), 3.72 (s, 3H), 2.91 (s, 2H), 2.29-2.13(m, 8H), 2.07 (s, 3H).

EXAMPLE 84N-(4-(aminomethyl)benzoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamideEXAMPLE 84A 4-(((tert-butoxycarbonyl)amino)methyl)benzoic acid

A solution of 4-(aminomethyl)benzoic acid (1.51 g, 10 mmol),di(tert-butyl) dicarbonate (2.62 g, 12 mmol), and sodium hydroxide (0.48g, 12 mmol) in tert-butanol (20 mL) was stirred for 16 hours, treatedwith water (200 mL), and extracted with hexanes. The aqueous layer wascooled to 5° C., adjusted to pH 4 with 1M NaHSO₄, and extracted withethyl acetate. The combined extracts were dried (Na₂SO₄), filtered, andconcentrated to provide the desired product.

MS (ESI(+)) m/z 252 (M+H)⁺, 269 (M+NH₄)⁺; ¹H NMR (DMSO-d₆) δ 8.06 (d,J=8.5 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H), 4.95 (br s, 1H), 4.40 (d, J=5.9Hz, 2H), 1.48 (s, 9H).

EXAMPLE 84BN-(4-(aminomethyl)benzoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide

The desired product was prepared by substituting Example 84A forN-(tert-butoxycarbonyl)-L-valine in Example 70.

MS (ESI(+)) m/z 510 (M+H)⁺; ¹H NMR (DMSO-d₆) δ8.35 (br s, 3H), 8.24 (m,1H), 7.74 (s, 1H), 7.68(m, 2H), 7.59 (m, 3H), 7.34 (m, 2H), 6.73 (m,1H), 6.57 (s, 2H), 3.95 (m, 2H), 3.88 (s, 3H), 3.64 (m, 6H), 3.56 (s,3H).

EXAMPLE 85 1,2,3-trimethoxy-5-((4-methoxybenzyl)sulfanyl)benzene EXAMPLE85A 3,4,5-trimethoxybenzenethiol

A room temperature suspension of zinc powder (430 mg, 6.56 mmol) anddichlorodimethylsilane (0.80 mL, 6.59 mmol) in 1,2-dichloroethane (15mL) was treated with a solution of 3,4,5-trimethoxybenzenesulfonylchloride (500 mg, 1.87 mmol) and 1,3-dimethyl-2-imidazolidinone (647 mg,5.67 mmol) in 1,2-dichloroethane (15 mL). The reaction was heated to 75°C. for 1 hour, cooled to room temperature, filtered, and concentrated.The concentrate was dissolved in methanol, concentrated, dissolved inmethanol, and concentrated. The concentrate was purified by flash columnchromatography on silica gel with dichloromethane to provide the desiredproduct.

EXAMPLE 85B 1,2,3-trimethoxy-5-((4-methoxybenzyl)sulfanyl)benzene

A room temperature solution of Example 85A (194 mg, 0.97 mmol),1-(chloromethyl)-4-methoxybenzene (162 mg, 1.03 mmol), and KOH (70 mg,1.25 mmol) in DMF (5 mL) was stirred for 2 hours, treated with saturatedNH₄Cl, and extracted with ethyl acetate. The combined extracts werewashed with brine, dried (MgSO₄), filtered, and concentrated. Theconcentrate was purified by flash column chromatography on silica gelwith 25% ethyl acetate/hexanes to provide the desired product.

mp 65-67° C.; MS (DCI/NH₃) m/e 321 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ7.27 (d, J=9 Hz, 2H), 6.87 (d, J=9 Hz, 2H), 6.59 (s, 2H), 4.19 (s, 2H),3.72 (s, 3H), 3.61 (s, 3H), 3.32 (s, 6H); Anal. calcd. for C₁₇H₂₀O₄S: C,63.72; H, 6.29. Found: C, 63.71; H, 6.39.

EXAMPLE 86 1,2,3-trimethoxy-5-((4-methoxybenzyl)sulfinyl)benzene

A room temperature mixture of Example 85B (100 mg, 0.31 mmol), aceticanhydride (38 mg, 0.37 mmol), and silica gel (65 mg) in dichloromethane(1.5 mL) was treated with 30% H₂O₂ (45 μL), stirred for 16 hours,filtered, and washed with dichloromethane. The filtrate was washedsequentially with 10% Na₂SO₃, saturated NaHCO₃, and brine, dried(Na₂SO₄), filtered, and concentrated. The concentrate was purified byflash column chromatography on silica gel with 1%methanol/dichloromethane to provide the desired product.

mp 103-105° C.; MS (DCI/NH₃) m/e 337 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ7.01 (d, J=9 Hz, 2H), 6.87 (d, J=9 Hz, 2H), 6.74 (s, 2H), 4.08 (dd, J=8Hz, 54 Hz, 2H), 3.72 (s, 3H), 3.68 (s, 3H), 3.32 (s, 6H); Anal. calcd.for C₁₇H₂₀O₅S: C, 60.70; H, 5.99. Found: C, 60.77; H, 5.82.

EXAMPLE 87 1,2,3-trimethoxy-5-((4-methoxybenzyl)sulfonyl)benzene

A solution of Example 85B (160 mg, 0.50 mmol) in acetone (3 mL) wastreated with water (3 mL), NaHCO₃ (500 mg), and potassiumperoxymonosulfate (OXONE®) (415 mg, 0.67 mmol), stirred for 3 hours,diluted with water, treated with solid Na₂SO₃, and extracted with ethylacetate. The combined extracts were washed with water and brine, dried(MgSO₄), filtered, and concentrated to provide the desired product.

mp 95-97° C.; MS (DCI/NH₃) m/e 370 (M+NH₄)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ7.09 (d, J=9 Hz, 2H), 6.91 (s, 2H), 6.87 (d, J=9 Hz, 2H), 4.58 (s, 2H),3.77 (s, 3H), 3.72 (s, 3H), 3.32 (s, 6H); Anal. calcd. for C₁₇H₂₀O₆S: C,57.94; H, 5.72. Found: C, 57.95; H, 5.68.

EXAMPLE 881,2,3-trimethoxy-5-((1-(4-methoxyphenyl)-1-methylethyl)sulfonyl)benzene

A 0° C. solution of Example 87 (105 mg, 0.30 mmol) in THF (2 mL) wastreated with 1.0M lithium hexamethyldisilazide in THF (0.36 mL, 0.36mmol), stirred for 15 minutes, treated with iodomethane (80 mg, 0.56mmol), stirred for 15 minutes, treated with a second portion of 1.0Mlithium hexamethyldisilazide in THF (0.36 mL, 0.36 mmol), stirred for 15minutes, treated with iodomethane (80 mg, 0.56 mmol), stirred for 15minutes, acidified with 10% HCl, and extracted with ethyl acetate. Thecombined extracts were washed with brine, dried (MgSO₄), filtered, andconcentrated. The concentrate was purified by flash columnchromatography on silica gel with 30% ethyl acetate/hexanes to providethe desired product.

MS (DCI/NH₃) m/e 398 (M+NH₄)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 7.27 (d, J=9Hz, 2H), 6.87 (d, J=9 Hz, 2H), 6.48 (s, 2H), 3.75 (s, 3H), 3.72 (s, 3H),3.63 (s, 6H), 1.70 (s, 6H); Anal. calcd. for C₁₉H₂₄O₆S: C, 59.98; H,6.36. Found: C, 59.71; H, 6.38.

EXAMPLE 89 2-methoxy-5-(((3,4,5-trimethoxyphenyl)sulfanyl)methyl)anilineEXAMPLE 89A1,2,3-trimethoxy-5-((4-methoxy-3-nitrobenzyl)sulfanyl)benzene

The desired product was prepared by substituting4-(chloromethyl)-2-nitrophenyl methyl ether for1-(chloromethyl)-4-methoxybenzene in Example 95.

EXAMPLE 89B2-methoxy-5-(((3,4,5-trimethoxyphenyl)sulfanyl)methyl)aniline

A room temperature suspension of zinc dust (2.35 g) in acetic acid (20mL) was treated dropwise with a solution of Example 89A (100 mg, 0.27mmol) and acetic acid (0.40 mL) in dichloromethane (1 mL), stirred atroom temperature for 30 minutes, diluted with ethyl acetate (100 mL),filtered, and concentrated. The concentrate was dissolved in ethylacetate, washed with saturated NaHCO₃ and brine, dried (MgSO₄),filtered, and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 5% ethyl acetate/dichloromethane toprovide the desired product.

MS (DCI/NH₃) m/e 336 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 6.70-6.65 (m,2H), 6.58 (s, 2H), 6.50 (m, 1H), 4.68 (s, 2H), 4.05 (s, 2H), 3.72 (s,6H), 3.71 (s, 3H), 3.63 (s, 3H).

EXAMPLE 90 2-methoxy-5-(((3,4,5-trimethoxyphenyl)sulfinyl)methyl)anilineEXAMPLE 90A1,2,3-trimethoxy-5-((4-methoxy-3-nitrobenzyl)sulfinyl)benzene

The desired product was prepared by substituting Example 99A for Example95B in Example 96.

EXAMPLE 90B2-methoxy-5-(((3,4,5-trimethoxyphenyl)sulfinyl)methyl)aniline

A room temperature solution of Example 90A (75 mg, 0.20 mmol) in ethanol(5 mL) was treated with 10% Pd/C (10 mg), stirred under a hydrogenatmosphere for 3 hours, heated to reflux, stirred for 3 hours, cooled toroom temperature, filtered through diatomaceous earth (Celite®), andconcentrated. The concentrate was purified by flash columnchromatography with 50% ethyl acetate/dichloromethane to provide thedesired product.

MS (DCI/NH₃) m/e 352 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 6.80 (s, 2H),6.71 (d, J=8 Hz, 1H), 6.50 (d, J=3 Hz, 1H), 6.31 (dd, J=3 Hz, 8 Hz, 1H),4.76 (s, 2H), 3.93 (dd, J=15 Hz, 45 Hz, 2H), 3.79 (s, 6H), 3.73 (s, 3H),3.70 (s, 3H); Anal. calcd. for C₁₇H₂₁NO₅S: C, 58.10; H, 6.02; N, 3.99.Found: C, 58.14; H, 5.92; N, 3.85.

EXAMPLE 91 2-methoxy-5-(((3,4,5-trimethoxyphenyl)sulfonyl)methyl)anilineEXAMPLE 91A1,2,3-trimethoxy-5-((4-methoxy-3-nitrobenzyl)sulfonyl)benzene

The desired product was prepared by substituting Example 89A for Example85B in Example 87.

EXAMPLE 91B2-methoxy-5-(((3,4,5-trimethoxyphenyl)sulfonyl)methyl)aniline

A solution of Example 91A (490 mg, 1.23 mmol) in methanol (10 mL) wastreated with SnCl₂.2H₂O (1.39 g; 6.17 mmol), heated to reflux for Ihour, and concentrated. The concentrate was partitioned betweensaturated NaHCO₃ and ethyl acetate, and the aqueous phase was extractedwith ethyl acetate. The combined extracts were dried (MgSO₄), filtered,and concentrated. The concentrate was purified by flash columnchromatography on silica gel with 10% ethyl acetate/dichloromethane toprovide the desired product.

MS (DCI/NH₃) m/e 385 (M+NH₄)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 6.92 (s, 2H),6.70 (d, J=8 Hz, 1H), 6.53 (d, J=3 Hz, 1H), 6.30 (dd, J=3 Hz, 8 Hz, 1H),4.76 (s, 2H), 4.44 (s, 2H), 3.79 (s, 6H), 3.73 (s, 6H).

EXAMPLE 922-methoxy-5-(1-methyl-1-((3,4,5-trimethoxyphenyl)sulfonyl)ethyl)anilineEXAMPLE 92A1,2,3-trimethoxy-5-((1-(4-methoxy-3-nitrophenyl)-1-methylethyl)sulfonyl)benzene

The desired product was prepared by substituting Example 91A for Example87 in Example 88.

EXAMPLE 92B2-methoxy-5-(1-methyl-1-((3,4,5-trimethoxyphenyl)sulfonyl)ethyl)aniline

The desired product was prepared by substituting Example 92A for Example90A in Example 90B.

MS (DCI/NH₃) m/e 413 (M+NH₄)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 6.72 (d, J=3Hz, 1H), 6.69 (d, J=8 Hz, 1H), 6.50 (s, 2H), 6.44 (dd, J=3 Hz, 9 Hz,1H), 4.71 (s, 2H), 3.76 (s, 3H), 3.72 (s, 3H), 3.64 (s, 6H), 1.63 (s,6H); Anal. calcd. for C₁₉H₂₅NO₆S: C, 57.70; H, 6.37; N, 3.54. Found: C,57.56; H, 6.27; N, 3.60.

EXAMPLE 93 1,2,3-trimethoxy-5-(((4-methoxyphenyl)sulfanyl)methyl)benzene

The desired product was prepared by substituting 4-methoxybenzenethioland 5-(chloromethyl)-1,2,3-trimethoxybenzene for Example 85A and1-(chloromethyl)-4-methoxybenzene, respectively, in Example 85B.

MS (DCI/NH₃) m/e 321 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 7.30 (d, J=8Hz, 2H), 6.89 (d, J=8 Hz, 2H), 6.51 (s, 2H), 4.02 (s, 2H), 3.73 (s, 3H),3.68 (s, 6H), 3.33 (s, 3H).

EXAMPLE 94 1,2,3-trimethoxy-5-(((4-methoxyphenyl)sulfonyl)methyl)benzene

The desired product was prepared by substituting Example 93 for Example85B in Example 87.

MS (DCI/NH₃) m/e 370 (M+NH₄)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ7.62 (d, J=8Hz, 2H), 7.11 (d, J=8 Hz, 2H), 6.38 (s, 2H), 4.51 (s, 2H), 3.85 (s, 3H),3.63 (s, 3H), 3.61 (s, 6H).

EXAMPLE 951,2,3-trimethoxy-5-(1-((4-methoxyphenyl)sulfonyl)-1-methylethyl)benzene

The desired product was prepared by substituting Example 94 for Example87 in Example 88.

MS (DCI/NH₃) m/e 398 (M+NH₄)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 7.31 (d, J=8Hz, 2H), 7.03 (d, J=8 Hz, 2H), 6.51 (s, 2H), 3.82 (s, 3H), 3.67 (s, 3H),3.65 (s, 6H), 1.69 (s, 6H).

EXAMPLE 96 2-methoxy-5-((3,4,5-trimethoxybenzyl)sulfonyl)aniline EXAMPLE96A sodium 4-methoxy-3-nitrobenzenesulfinate

A solution of Na₂SO₃ (400 mg, 3.2 mmol) and NaHCO₃ (270 mg, 3.2 mmol) inH₂O (10 mL) was treated slowly with a solution of4-methoxy-3-nitrobenzenesulfonyl chloride (400 mg, 1.6 mmol) in acetone(3 mL), heated to 50° C. for 2 hours, cooled to room temperature, andwashed with dichloromethane. The aqueous wash was filtered throughcotton, lyophilized, suspended in methanol, filtered, concentrated, anddried under vacuum to provide the desired product.

EXAMPLE 96B1,2,3-trimethoxy-5-(((4-methoxy-3-nitrophenyl)sulfonyl)methyl)benzene

A suspension of Example 96A (380 mg, 1.6 mmol) in DMF (10 mL) wastreated slowly with a solution of5-(chloromethyl)-1,2,3-trimethoxybenzene (344 mg, 1.6 mmol) in DMF (5mL), heated to 120° C. for hour, cooled to room temperature, andpartitioned between ethyl acetate and brine. The aqueous layer wasextracted with ethyl acetate, and the combined extracts were washed withwater and brine, dried (MgSO₄), filtered, and concentrated. Theconcentrate was purified by flash column chromatography on silica gelwith 10% ethyl acetate/dichloromethane to provide the desired product.

EXAMPLE 96C 2-methoxy-5-((3,4,5-trimethoxybenzyl)sulfonyl)aniline

The desired product was prepared by substituting Example 96B for Example90A in Example 90B.

MS (DCI/NH₃) m/e 385 (M+NH₄)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 6.98-6.85 (m,3H), 6.37 (s, 2H), 5.21 (s, 2H), 4.38 (s, 2H), 3.84 (s, 3H), 3.63 (s,9H); Anal. calcd. for C₁₇H₂₁NO₆S: C, 55.57; H, 5.76; N, 3.81. Found: C,55.52; H, 5.77; N, 3.49.

EXAMPLE 972-methoxy-5-((1-methyl-1-(3,4,5-trimethoxyphenyl)ethyl)sulfonyl)anilineEXAMPLE 97A 12,3-trimethoxy-5-(1-((4-methoxy-3-nitrophenyl)sulfonyl)-1-methylethyl)benzene

The desired product was prepared by substituting Example 96B for Example87 in Example 88.

EXAMPLE 97B2-methoxy-5-((1-methyl-1-(3,4,5-trimethoxyphenyl)ethyl)sulfonyl)aniline

The desired product was prepared by substituting Example 97A for Example90A in Example 90B.

MS (DCI/NH₃) m/e 413 (M+NH₄)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 6.87 (d, J=8Hz, 1H), 6.78 (d, J=8 Hz, 1H), 6.59 (dd, J=3 Hz, 8 Hz, 1H), 6.51 (s,2H), 5.13 (s, 2H), 3.82 (s, 3H), 3.67 (s, 9H), 1.69 (s, 6H).

EXAMPLE 98 1,2,3-trimethoxy-5-((phenylsulfonyl)methyl)benzene

The desired product was prepared by substituting sodium benzenesulfinatefor Example 96A in Example 96B.

MS (DCI/NH₃) m/e 340 (M+NH₄)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 7.72-7.57 (m,5H), 6.38 (s, 2H), 4.58 (s, 2H), 3.64 (s, 3H), 3.40 (s, 6H).

Following Scheme 1 and the examples described above, the followingcompounds can be prepared:

EXAMPLE 99N-(2-aminoacetyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamideEXAMPLE 100N-(2-aminoacetyl)-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamideEXAMPLE 101N-((2S)-2-aminopropanoyl]-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamideEXAMPLE 102N-((2S)-2-aminopropanoyl-1-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamideEXAMPLE 103N-(3-aminopropanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamideEXAMPLE 104N-(3-aminopropanoyl)-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamideEXAMPLE 105(2S)-2-amino-N-((1S)-1-methyl-2-oxo-2-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)ethyl)propanamideEXAMPLE 106(2S)-2-amino-N-((1S)-1-methyl-2-((1-methyl-1H-indol-5-yl)((3,4,5-trimethoxyphenyl)sulfonyl)amino)-2-oxoethyl)propanamideEXAMPLE 107N-((2S)-2-amino-3-hydroxypropanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamideEXAMPLE 108N-((2S)-2-amino-3-hydroxypropanoyl)-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide

1. A compound having formula (I)

or pharmaceutically acceptable salts or prodrugs thereof, wherein L¹ isselected from the group consisting of (1) —S(O)₂O—, (2) —OS(O)₂—, (3)—NR⁷SO₂—, wherein R⁷ is selected from the group consisting of (a)hydrogen, (b) hydroxy, (c) amidinyl, (d) a nitrogen-protecting group,(e) alkanoyl, (f) alkyl, (g) alkenyl, (h) alkynyl, (i) cycloalkyl, (j)cycloalkylalkyl, (k) cycloalkenyl, (l) cycloalkenylalkyl, (m) aryloyl,(n) alkoxy, wherein (e)-(n) can be optionally substituted with one, two,or three substituents independently selected from the group consistingof (i) hydroxyl, (ii) halo, (iii) cyano, (iv) azido, (v) carboxy, (vi)amidinyl, (vii) alkyl, (viii) aryl, (ix) oxo, (x) heteroaryl, (xi)heterocycloalkyl, (xii) —NR^(c)R^(d), wherein R^(c) and R^(d) areindependently selected from the group consisting of (1′) hydrogen, (2′)alkyl, (3′) aryl, and (4′) alkoxyalkyl, and (xiii)-(alkylene)—NR^(c)R^(d), wherein for (x) and (xi), the heteroaryl andthe heterocycloalkyl can be optionally substituted with 1, 2, or 3substituents independently selected from the group consisting of (1′)alkyl, and (2′) a nitrogen protecting group, (o) heterocycloalkyloyl,wherein the heterocycloalkyloyl can be optionally substituted with 1, 2,or 3 substituents independently selected from the group consisting of(i) alkyl, and (ii) a nitrogen protecting group, and (p)—(CH₂)_(x)NR^(A)R^(B), wherein x is 0-6, and R^(A) and R^(B) areindependently selected from the group consisting of (i) hydrogen, (ii)alkyl, (iii) alkenyl, (iv) alkynyl, (v) cycloalkyl, (vi)cycloalkylalkyl, (vii) cycloalkenyl, and (viii) cycloalkenylalkyl, (4)—SO₂NR⁷—, wherein R⁷ is defined above, (5) —S(O)CR¹²R¹³—, wherein R¹²and R¹³ are independently selected from the group consisting of (a)hydrogen, (b) alkyl, (c) alkenyl, and (d) alkynyl, (6) —SO₂CR¹²R¹³—, (7)—SCR¹²R¹³—, (8) —CR¹²R¹³S(O)—, (9) —CR¹²R¹³SO₂—, and (10) —CR¹²R¹³S—,wherein (1)-(10) are shown with their left ends attached to R¹ and theirright ends attached to the phenyl ring; R¹ is aryl or heteroaryl,wherein the aryl or the heteroaryl can be optionally substituted with 1,2, 3, 4,or 5 substituents independently selected from the groupconsisting of (a) oxo, (b) azido, (c) carboxy, (d) carboxaldehyde, (e)cyano, (f) halo, (g) hydroxy, (h) nitro, (i) perfluoroalkyl, (j)perfluoroalkoxy, (k) alkyl, (l) alkenyl, (m) alkynyl, (n) alkanoyloxy,(o) alkoxycarbonyl, (p) cycloalkyl, (q) cycloalkylalkyl, (r)cycloalkenyl, (s) cycloalkenylalkyl, (t) alkanoyl, (u) alkoxy, (v)cycloalkoxy, (w) aryloxy, (x) heteroaryloxy, (y) thioalkoxy (z)alkylsulfinyl, (aa) alkylsulfonyl, (bb) —NR⁸R⁹, wherein R⁸ and R⁹ areindependently selected from the group consisting of (i) hydrogen (ii)alkyl, (iii) arylalkyl, and (iv) alkanoyl, wherein the alkanoyl can beoptionally substituted with 1 or 2 substituents independently selectedfrom the group consisting of (1′) halo (2′) hydroxy, and (3′) —NR¹⁰R¹¹wherein R¹⁰ and R¹¹ are independently hydrogen or alkyl, and (cc)—SO₂NR⁸R⁹, wherein R⁸ and R⁹ are defined above; R² and R⁶ areindependently selected from the group consisting of (1) hydrogen, (2)alkyl, (3) alkoxy, (4) thioalkoxy; and (5) hydroxy, and R³, R⁴, and R⁵are independently selected from the group consisting of (1) alkyl, (2)alkoxy, (3) thioalkoxy, and (4) hydroxy; all of the foregoing with theproviso that combinations wherein L¹ is —NR⁷SO₂— and R¹ is (1)unsubstituted or substituted 1H-indoly-7-yl, (2) phenyl which is2-monosubstituted with —NR⁸R⁹, (3) pyrid-3-yl which is 2-monosubstitutedwith —NR⁸R⁹, or (4) pyrimidin-5-yl which is 4-monosubstituted with—NR⁸R⁹, are excluded therefrom.
 2. A compound according to claim 1,wherein L¹ is —SO₂NR⁷—, and R⁷ is defined above.
 3. A compound accordingto claim 2, wherein R² and R⁶ are hydrogen, and R³, R⁴, and R⁵ aremethoxy.
 4. A compound according to claim 3, wherein R¹ is optionallysubstituted aryl.
 5. A compound according to claim 4 selected from thegroup consisting of4-methoxy-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,3,4-dimethoxy-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,4-trifluoromethoxy-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,4-trifluoromethyl-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,4-nitro-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,4-amino-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,4-((2-chloroacetyl)amino)-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,2-nitro-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,4-methoxy-3-nitro-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,3-amino-4-methoxy-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide, and3-amino-4-methoxy-N-methyl-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide.6. A compound according to claim 3, wherein R¹ is optionally substitutedheteroaryl.
 7. A compound according to claim 6, wherein R¹ is optionallysubstituted 2,3-dihydro-1H-indol-5-yl.
 8. A compound according to claim7 selected from the group consisting of1-formyl-N-(3,4,5-trimethoxyphenyl)indoline-5-sulfonamide,N-(3,4,5-trimethoxyphenyl)indoline-5-sulfonamide, and1-methyl-N-(3,4,5-trimethoxyphenyl)indoline-5-sulfonamide.
 9. A compoundaccording to claim 6, wherein R¹ is optionally substituted1H-indol-3-yl.
 10. A compound according to claim 9 selected from thegroup consisting of5-nitro-N-(3,4,5-trimethoxyphenyl)-1H-indole-3-sulfonamide,1-methyl-5-nitro-N-(3,4,5-trimethoxyphenyl)-1H-indole-3-sulfonamide,5-amino-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-3-sulfonamide, and5-amino-N-(3,4,5-trimethoxyphenyl)-1H-indole-3-sulfonamide.
 11. Acompound according to claim 6, wherein R¹ is optionally substituted1H-indol-5-yl.
 12. A compound according to claim 11 selected from thegroup consisting of N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N,1-dimethyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,1-ethyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-(2-hydroxyethyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-(2-fluoroethyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-ethyl-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-((dimethylamino)acetyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,1-methyl-N-(((2S)-1-methylpyrrolidinyl)carbonyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-((2S)-2-(dimethylamino)-3-methylbutanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-((2S)-2-amino-3-methylbutanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,1-methyl-N-((2S)-2-methylamino)propanoyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-((²S)-2-amino-2-phenylethanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-((2S)-2-amino-3-phenylpropanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,1-methyl-N-((2S)-pyrrolidinylcarbonyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-((2S)-2,6-diaminohexanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-((2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,(2S)-2-amino-4-oxo-4-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)butanoicacid,(3S)-3-amino-4-oxo-4-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)butanoicacid,(2S)-2-amino-5-oxo-5-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)pentanoicacid,(4S)-4-amino-5-oxo-5-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)pentanoicacid,N-((bis(2-methoxyethyl)amino)acetyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,1-methyl-N-(4-morpholinylacetyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,1-methyl-N-((4-methyl-1-piperazinyl)acetyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-(4-(aminomethyl)benzoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-(2-aminoacetyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-((²S)-2-aminopropanoyl]-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-(3-aminopropanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,(2S)-2-amino-N-((1S)-1-methyl-2-oxo-2-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)ethyl)propanamide,andN-((2S)-2-amino-3-hydroxypropanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide.13. A compound according to claim 1, wherein L¹ is —NR⁷SO₂—, and R⁷ isdefined above.
 14. A compound according to claim 13, wherein R² and R⁶are hydrogen, and R³, R⁴, and R⁵ are methoxy.
 15. A compound accordingto claim 14 selected from the group consisting of3,4,5-trimethoxy-N-(4-methoxyphenyl)benzenesulfonamide,N-(3-hydroxy-4-methoxyphenyl)-3,4,5-trimethoxybenzenesulfonamide,N-(1-methyl-1H-indol-5-yl)-3,4,5-trimethoxybenzenesulfonamide,N-(4-(dimethylamino)phenyl)-3,4,5-trimethoxybenzenesulfonamide,N-(4-fluoro-3-methoxyphenyl)-3,4,5-trimethoxybenzenesulfonamide,3,4,5-trimethoxy-N-(4-(trifluoromethoxy)phenyl)benzenesulfonamide,3,4,5-trimethoxy-N-(2,3,4,5,6-pentafluorophenyl)benzenesulfonamide,N-(3-amino-4-methoxyphenyl)-3,4,5-trimethoxybenzenesulfonamide,3,4,5-trimethoxy-N-(1-methyl-1H-indol-4-yl)benzenesulfonamide,3,4,5-trimethoxy-N-(1-methyl-1H-indol-6-yl)benzenesulfonamide,N-(1H-indol-5-yl)-3,4,5-trimethoxybenzenesulfonamide,N-(1,2-dimethyl-1H-indol-5-yl)-3,4,5-trimethoxybenzenesulfonamide,N-(3-chloro-1H-indol-5-yl)-3,4,5-trimethoxybenzenesulfonamide,N-(1H-indazol-5-yl)-3,4,5-trimethoxybenzenesulfonamide,3,4,5-trimethoxy-N-(1-methyl-1H-benzimidazol-6-yl) benzenesulfonamide,3,4,5-trimethoxy-N-(1-methyl-1H-benzimidazol-5-yl)benzenesulfonamide,3,4,5-trimethoxy-N-methyl-N-(1-methyl-1H-indol-5-yl) benzenesulfonamide,3,4,5-trimethoxy-N-(2-(dimethylamino)ethyl)-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,tert-butyl2-((1-methyl-1H-indol-5-yl)((3,4,5-trimethoxyphenyl)sulfonyl)amino)ethylcarbamate,N-(2-hydroxyethyl)-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,N-(2,3-dihydro-1,4-benzodioxin-6-yl)-3,4,5-trimethoxybenzenesulfonamide,N-(2-aminoethyl)-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,N-acetyl-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,3,4,5-trimethoxy-N-(6-quinolinyl)benzenesulfonamide,N-(2-aminoacetyl)-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,N-((2S)-2-aminopropanoyl]-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,N-(3-aminopropanoyl)-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,(2S)-2-amino-N-((1S)-1-methyl-2-((1-methyl-1H-indol-5-yl)((3,4,5-trimethoxyphenyl)sulfonyl)amino)-2-oxoethyl)propanamide,andN-((2S)-2-amino-3-hydroxypropanoyl)-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide.16. A compound according to claim 1, wherein L¹ is —OSO₂—.
 17. Acompound according to claim 16, wherein R² and R⁶ are hydrogen, and R³,R⁴, and R⁵ are methoxy.
 18. A compound according to claim 17 selectedfrom the group consisting of 1H-indol-5-yl3,4,5-trimethoxybenzenesulfonate, 1H-indol-5-yl3,4,5-trimethoxybenzenesulfonate, 4-methylphenyl3,4,5-trimethoxybenzenesulfonate, 4-methoxyphenyl3,4,5-trimethoxybenzenesulfonate,4-nitrophenyl-3,4,5-trimethoxybenzenesulfonate,4-aminophenyl-3,4,5-trimethoxybenzenesulfonate,4-dimethylaminophenyl-3,4,5-trimethoxybenzenesulfonate, and1-methyl-2-oxo-1,2-dihydro-4-pyridinyl 3,4,5-trimethoxybenzenesulfonate.19. A compound according to claim 1, wherein L¹ is —SO₂O—.
 20. Acompound according to claim 19, wherein R² and R⁶ are hydrogen, and R³,R⁴, and R⁵ are methoxy.
 21. A compound according to claim 20 selectedfrom the group consisting of (3,4,5-trimethoxyphenyl)4-methoxybenzenesulfonate, 3,4,5-trimethoxyphenyl)4-methylbenzenesulfonate, 3,4,5-trimethoxyphenyl)3-amino-4-methoxybenzenesulfonate,(3,4,5-trimethoxyphenyl)-4-(dimethylamino)benzenesulfonate,3,4,5-trimethoxyphenyl 1-methyl-5-indolinesulfonate,3,4,5-trimethoxyphenyl 6-methoxy-3-pyridinesulfonate,3,4,5-trimethoxyphenyl3-((3-aminopropanoyl)amino)-4-methoxybenzenesulfonate,3,4,5-trimethoxyphenyl3-(((2R)-2-aminopropanoyl)amino)-4-methoxybenzenesulfonate, and3,4,5-trimethoxyphenyl3-(((2R)-2-amino-3-methylbutanoyl)amino)-4-methoxybenzenesulfonate. 22.A compound according to claim 1, wherein L¹ is selected from the groupconsisting of —SO₂CR¹²R¹³—, —SCR¹²R¹³—, —CR¹²R¹³S(O)—, —CR¹²R¹³SO₂—, and—CR¹² R¹³S—.
 23. A compound according to claim 22 selected from thegroup consisting of1,2,3-trimethoxy-5-((4-methoxybenzyl)sulfanyl)benzene,1,2,3-trimethoxy-5-((4-methoxybenzyl)sulfinyl)benzene,1,2,3-trimethoxy-5-((4-methoxybenzyl)sulfonyl)benzene,1,2,3-trimethoxy-5-((1-(4-methoxyphenyl)-1-methylethyl)sulfonyl)benzene,2-methoxy-5-(((3,4,5-trimethoxyphenyl)sulfanyl)methyl)aniline,2-methoxy-5-(((3,4,5-trimethoxyphenyl)sulfinyl)methyl)aniline,2-methoxy-5-(((3,4,5-trimethoxyphenyl)sulfonyl)methyl)aniline,2-methoxy-5-(1-methyl-1-((3,4,5-trimethoxyphenyl)sulfonyl)ethyl)aniline,1,2,3-trimethoxy-5-(((4-methoxyphenyl)sulfanyl)methyl)benzene,1,2,3-trimethoxy-5-(((4-methoxyphenyl)sulfonyl)methyl)benzene,1,2,3-trimethoxy-5-(1-((4-methoxyphenyl)sulfonyl)-1-methylethyl)benzene,2-methoxy-5-((3,4,5-trimethoxybenzyl)sulfonyl)aniline,2-methoxy-5-((1-methyl-1-(3,4,5-trimethoxyphenyl)ethyl)sulfonyl)aniline,and 1,2,3-trimethoxy-5-((phenylsulfonyl)methyl)benzene.
 24. A method ofinhibiting polymerization of tubulin in a mammal in recognized need ofsuch treatment comprising administering an effective amount of acompound of claim
 1. 25. A method of treating cancer in a mammal inrecognized need of such treatment comprising administering an effectiveamount of a compound of claim
 1. 26. A compound selected from the groupconsisting of 4-methoxy-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,3,4-dimethoxy-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,4-trifluoromethoxy-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,4-trifluoromethyl-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,4-nitro-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,4-amino-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,4-((2-chloroacetyl)amino)-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,2-nitro-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,4-methoxy-3-nitro-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,3-amino-4-methoxy-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,1-formyl-N-(3,4,5-trimethoxyphenyl)indoline-5-sulfonamide,N-(3,4,5-trimethoxyphenyl)indoline-5-sulfonamide,5-nitro-N-(3,4,5-trimethoxyphenyl)-1H-indole-3-sulfonamide,1-methyl-N-(3,4,5-trimethoxyphenyl)indoline-5-sulfonamide,1-methyl-5-nitro-N-(3,4,5-trimethoxyphenyl)-1H-indole-3-sulfonamide,5-amino-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-3-sulfonamide,5-amino-N-(3,4,5-trimethoxyphenyl)-1H-indole-3-sulfonamide,N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N,1-dimethyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,3,4,5-trimethoxy-N-(4-methoxyphenyl)benzenesulfonamide,N-(3-hydroxy-4-methoxyphenyl)-3,4,5-trimethoxybenzenesulfonamide,N-(1-methyl-1H-indol-5-yl)-3,4,5-trimethoxybenzenesulfonamide,N-(4-(dimethylamino)phenyl)-3,4,5-trimethoxybenzenesulfonamide,N-(4-fluoro-3-methoxyphenyl)-3,4,5-trimethoxybenzenesulfonamide,3,4,5-trimethoxy-N-(4-(trifluoromethoxy)phenyl)benzenesulfonamide,3,4,5-trimethoxy-N-(2,3,4,5,6-pentafluorophenyl)benzenesulfonamide,N-(3-amino-4-methoxyphenyl)-3,4,5-trimethoxybenzenesulfonamide,3,4,5-trimethoxy-N-(1-methyl-1H-indol-4-yl)benzenesulfonamide,3,4,5-trimethoxy-N-(1-methyl-1H-indol-6-yl)benzenesulfonamide,N-(1H-indol-5-yl)-3,4,5-trimethoxybenzenesulfonamide,N-(1,2-dimethyl-1H-indol-5-yl)-3,4,5-trimethoxybenzenesulfonamide,N-(3-chloro-1H-indol-5-yl)-3,4,5-trimethoxybenzenesulfonamide,N-(1H-indazol-5-yl)-3,4,5-trimethoxybenzenesulfonamide,3,4,5-trimethoxy-N-(1-methyl-1H-benzimidazol-6-yl) benzenesulfonamide,3,4,5-trimethoxy-N-(1-methyl-1H-benzimidazol-5-yl)benzenesulfonamide,3,4,5-trimethoxy-N-methyl-N-(1-methyl-1H-indol-5-yl) benzenesulfonamide,3,4,5-trimethoxy-N-(2-(dimethylamino)ethyl)-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,1H-indol-5-yl 3,4,5-trimethoxybenzenesulfonate, (3,4,5-trimethoxyphenyl)4-methoxybenzenesulfonate, 3,4,5-trimethoxyphenyl)4-methylbenzenesulfonate, 1H-indol-5-yl3,4,5-trimethoxybenzenesulfonate, 3,4,5-trimethoxyphenyl)3-amino-4-methoxybenzenesulfonate,(3,4,5-trimethoxyphenyl)-4-(dimethylamino)benzenesulfonate,4-methylphenyl 3,4,5-trimethoxybenzenesulfonate, 3,4,5-trimethoxyphenyl1-methyl-5-indolinesulfonate, and 4-methoxyphenyl3,4,5-trimethoxybenzenesulfonate, tert-butyl2-((1-methyl-1H-indol-5-yl)((3,4,5-trimethoxyphenyl)sulfonyl)amino)ethylcarbamate,N-(2-hydroxyethyl)-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,N-(2,3-dihydro-1,4-benzodioxin-6-yl)-3,4,5-trimethoxybenzenesulfonamide,N-(2-aminoethyl)-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,3-amino-4-methoxy-N-methyl-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,1-ethyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-acetyl-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,3,4,5-trimethoxy-N-(6-quinolinyl)benzenesulfonamide,N-(2-hydroxyethyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-(2-fluoroethyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-ethyl-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,4-nitrophenyl-3,4,5-trimethoxybenzenesulfonate,4-aminophenyl-3,4,5-trimethoxybenzenesulfonate,4-dimethylaminophenyl-3,4,5-trimethoxybenzenesulfonate,3,4,5-trimethoxyphenyl 6-methoxy-3-pyridinesulfonate,1-methyl-2-oxo-1,2-dihydro-4-pyridinyl 3,4,5-trimethoxybenzenesulfonate,3,4,5-trimethoxyphenyl3-((3-aminopropanoyl)amino)-4-methoxybenzenesulfonate,3,4,5-trimethoxyphenyl3-(((2R)-2-aminopropanoyl)amino)-4-methoxybenzenesulfonate,3,4,5-trimethoxyphenyl3-(((2R)-2-amino-3-methylbutanoyl)amino)-4-methoxybenzenesulfonate,N-((dimethylamino)acetyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,1-methyl-N-(((2S)-1-methylpyrrolidinyl)carbonyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-((2S)-2-(dimethylamino)-3-methylbutanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-((2S)-2-amino-3-methylbutanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,1-methyl-N-((2S)-2-methylamino)propanoyl)-N-(3,4,5-trimethoxyphenyl)1H-indole-5-sulfonamide,N-((2S)-2-amino-2-phenylethanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-((2S)-2-amino-3-phenylpropanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,1-methyl-N-((2S)-pyrrolidinylcarbonyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-((2S)-2,6-diaminohexanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-((2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,(2S)-2-amino-4-oxo-4-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)butanoicacid,(3S)-3-amino-4-oxo-4-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)butanoicacid,(2S)-2-amino-5-oxo-5-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)pentanoicacid,(4S)-4-amino-5-oxo-5-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)pentanoicacid,N-((bis(2-methoxyethyl)amino)acetyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,1-methyl-N-(4-morpholinylacetyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,1-methyl-N-((4-methyl-1-piperazinyl)acetyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-(4-(aminomethyl)benzoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,1,2,3-trimethoxy-5-((4-methoxybenzyl)sulfanyl)benzene,1,2,3-trimethoxy-5-((4-methoxybenzyl)sulfinyl)benzene,1,2,3-trimethoxy-5-((4-methoxybenzyl)sulfonyl)benzene,1,2,3-trimethoxy-5-((1-(4-methoxyphenyl)-1-methylethyl)sulfonyl)benzene,2-methoxy-5-(((3,4,5-trimethoxyphenyl)sulfanyl)methyl)aniline,2-methoxy-5-(((3,4,5-trimethoxyphenyl)sulfinyl)methyl)aniline,2-methoxy-5-(((3,4,5-trimethoxyphenyl)sulfonyl)methyl)aniline,2-methoxy-5-(1-methyl-1-((3,4,5-trimethoxyphenyl)sulfonyl)ethyl)aniline,1,2,3-trimethoxy-5-(((4-methoxyphenyl)sulfanyl)methyl)benzene,1,2,3-trimethoxy-5-(((4-methoxyphenyl)sulfonyl)methyl)benzene,1,2,3-trimethoxy-5-(1-((4-methoxyphenyl)sulfonyl)-1-methylethyl)benzene,2-methoxy-5-((3,4,5-trimethoxybenzyl)sulfonyl)aniline,2-methoxy-5-((1-methyl-1-(3,4,5-trimethoxyphenyl)ethyl)sulfonyl)aniline,1,2,3-trimethoxy-5-((phenylsulfonyl)methyl)benzene,N-(2-aminoacetyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-(2-aminoacetyl)-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,N-((2S)-2-aminopropanoyl]-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-((2S)-2-aminopropanoyl]-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,N-(3-aminopropanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-(3-aminopropanoyl)-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,(2S)-2-amino-N-((1S)-1-methyl-2-oxo-2-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)ethyl)propanamide,(2S)-2-amino-N-((1S)-1-methyl-2-((1-methyl-1H-indol-5-yl)((3,4,5-trimethoxyphenyl)sulfonyl)amino)-2-oxoethyl)propanamide,N-((2S)-2-amino-3-hydroxypropanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,andN-((2S)-2-amino-3-hydroxypropanoyl)-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide.27. A compound selected from the group consisting of4-methoxy-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,3,4-dimethoxy-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,4-trifluoromethoxy-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,4-trifluoromethyl-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,4-nitro-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,4-amino-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,4-((2-chloroacetyl)amino)-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,2-nitro-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,4-methoxy-3-nitro-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,3-amino-4-methoxy-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,1-formyl-N-(3,4,5-trimethoxyphenyl)indoline-5-sulfonamide,N-(3,4,5-trimethoxyphenyl)indoline-5-sulfonamide,5-nitro-N-(3,4,5-trimethoxyphenyl)-1H-indole-3-sulfonamide,1-methyl-N-(3,4,5-trimethoxyphenyl)indoline-5-sulfonamide,1-methyl-5-nitro-N-(3,4,5-trimethoxyphenyl)-1H-indole-3-sulfonamide,5-amino-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-3-sulfonamide,5-amino-N-(3,4,5-trimethoxyphenyl)-1H-indole-3-sulfonamide,N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N,1-dimethyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,3,4,5-trimethoxy-N-(4-methoxyphenyl)benzenesulfonamide,N-(3-hydroxy-4-methoxyphenyl)-3,4,5-trimethoxybenzenesulfonamide,N-(1-methyl-1H-indol-5-yl)-3,4,5-trimethoxybenzenesulfonamide,N-(4-(dimethylamino)phenyl)-3,4,5-trimethoxybenzenesulfonamide,N-(4-fluoro-3-methoxyphenyl)-3,4,5-trimethoxybenzenesulfonamide,3,4,5-trimethoxy-N-(4-(trifluoromethoxy)phenyl)benzenesulfonamide,3,4,5-trimethoxy-N-(2,3,4,5,6-pentafluorophenyl)benzenesulfonamide,N-(3-amino-4-methoxyphenyl)-3,4,5-trimethoxybenzenesulfonamide,3,4,5-trimethoxy-N-(1-methyl-1H-indol-4-yl)benzenesulfonamide,3,4,5-trimethoxy-N-(1-methyl-1H-indol-6-yl)benzenesulfonamide,N-(1H-indol-5-yl)-3,4,5-trimethoxybenzenesulfonamide,N-(1,2-dimethyl-1H-indol-5-yl)-3,4,5-trimethoxybenzenesulfonamide,N-(3-chloro-1H-indol-5-yl)-3,4,5-trimethoxybenzenesulfonamide,N-(1H-indazol-5-yl)-3,4,5-trimethoxybenzenesulfonamide,3,4,5-trimethoxy-N-(1-methyl-1H-benzimidazol-6-yl) benzenesulfonamide,3,4,5-trimethoxy-N-(1-methyl-1H-benzimidazol-5-yl)benzenesulfonamide,3,4,5-trimethoxy-N-methyl-N-(1-methyl-1H-indol-5-yl) benzenesulfonamide,3,4,5-trimethoxy-N-(2-(dimethylamino)ethyl)-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,1H-indol-5-yl 3,4,5-trimethoxybenzenesulfonate, (3,4,5-trimethoxyphenyl)4-methoxybenzenesulfonate, 3,4,5-trimethoxyphenyl)4-methylbenzenesulfonate, 1H-indol-5-yl3,4,5-trimethoxybenzenesulfonate, 3,4,5-trimethoxyphenyl)3-amino-4-methoxybenzenesulfonate,(3,4,5-trimethoxyphenyl)-4-(dimethylamino)benzenesulfonate,4-methylphenyl 3,4,5-trimethoxybenzenesulfonate, 3,4,5-trimethoxyphenyl1-methyl-5-indolinesulfonate, and 4-methoxyphenyl3,4,5-trimethoxybenzenesulfonate, tert-butyl2-((1-methyl-1H-indol-5-yl)((3,4,5-trimethoxyphenyl)sulfonyl)amino)ethylcarbamate,N-(2-hydroxyethyl)-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,N-(2,3-dihydro-1,4-benzodioxin-6-yl)-3,4,5-trimethoxybenzenesulfonamide,N-(2-aminoethyl)-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,3-amino-4-methoxy-N-methyl-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,1-ethyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-acetyl-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,3,4,5-trimethoxy-N-(6-quinolinyl)benzenesulfonamide,N-(2-hydroxyethyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-(2-fluoroethyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-ethyl-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,4-nitrophenyl-3,4,5-trimethoxybenzenesulfonate,4-aminophenyl-3,4,5-trimethoxybenzenesulfonate,4-dimethylaminophenyl-3,4,5-trimethoxybenzenesulfonate,3,4,5-trimethoxyphenyl 6-methoxy-3-pyridinesulfonate,1-methyl-2-oxo-1,2-dihydro-4-pyridinyl 3,4,5-trimethoxybenzenesulfonate.3,4,5-trimethoxyphenyl3-((3-aminopropanoyl)amino)-4-methoxybenzenesulfonate,3,4,5-trimethoxyphenyl3-(((2R)-2-aminopropanoyl)amino)-4-methoxybenzenesulfonate,3,4,5-trimethoxyphenyl3-(((2R)-2-amino-3-methylbutanoyl)amino)-4-methoxybenzenesulfonate,N-((dimethylamino)acetyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,1-methyl-N-(((2S)-1-methylpyrrolidinyl)carbonyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-((2S)-2-(dimethylamino)-3-methylbutanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-((2S)-2-amino-3-methylbutanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,1-methyl-N-((2S)-2-methylamino)propanoyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-((2S)-2-amino-2-phenylethanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-((2S)-2-amino-3-phenylpropanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,1-methyl-N-((2S)-pyrrolidinylcarbonyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-((2S)-2,6-diaminohexanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-((2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,(2S)-2-amino-4-oxo-4-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)butanoicacid,(3S)-3-amino-4-oxo-4-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)butanoicacid,(2S)-2-amino-5-oxo-5-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)pentanoicacid,(4S)-4-amino-5-oxo-5-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)pentanoicacid,N-((bis(2-methoxyethyl)amino)acetyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,1-methyl-N-(4-morpholinylacetyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,1-methyl-N-((4-methyl-1-piperazinyl)acetyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,N-(4-(aminomethyl)benzoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,1,2,3-trimethoxy-5-((4-methoxybenzyl)sulfanyl)benzene,1,2,3-trimethoxy-5-((4-methoxybenzyl)sulfinyl)benzene,1,2,3-trimethoxy-5-((4-methoxybenzyl)sulfonyl)benzene,1,2,3-trimethoxy-5-((1-(4-methoxyphenyl)-1-methylethyl)sulfonyl)benzene,2-methoxy-5-(((3,4,5-trimethoxyphenyl)sulfanyl)methyl)aniline,2-methoxy-5-(((3,4,5-trimethoxyphenyl)sulfinyl)methyl)aniline,2-methoxy-5-(((3,4,5-trimethoxyphenyl)sulfonyl)methyl)aniline,2-methoxy-5-(1-methyl-1-((3,4,5-trimethoxyphenyl)sulfonyl)ethyl)aniline,1,2,3-trimethoxy-5-(((4-methoxyphenyl)sulfanyl)methyl)benzene,1,2,3-trimethoxy-5-(((4-methoxyphenyl)sulfonyl)methyl)benzene,1,2,3-trimethoxy-5-(1-((4-methoxyphenyl)sulfonyl)-1-methylethyl)benzene,2-methoxy-5-((3,4,5-trimethoxybenzyl)sulfonyl)aniline,2-methoxy-5-((1-methyl-1-(3,4,5-trimethoxyphenyl)ethyl)sulfonyl)aniline,and 1,2,3-trimethoxy-5-((phenylsulfonyl)methyl)benzene.
 28. A compoundwhich isN-((dimethylamino)acetyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide.